GSDMD knockout alleviates sepsis-associated skeletal muscle atrophy by inhibiting IL18/AMPK signaling.

BACKGROUND: Sepsis commonly leads to skeletal muscle atrophy, characterized by substantial muscle weakness and degeneration, ultimately contributing to an adverse prognosis. Studies have shown that programmed cell death is an important factor in the progression of muscle loss in sepsis. However, the precise role and mechanism of pyroptosis in skeletal muscle atrophy are not yet fully comprehended. Therefore, we aimed to examine the role and mechanism of action of the pyroptosis effector protein GSDMD in recognized cellular and mouse models of sepsis. METHODS: The levels of GSDMD and N-GSDMD in skeletal muscle were evaluated 2, 4, and 8 days after CLP. Sepsis was produced in mice that lacked the Gsdmd gene (Gsdmd knockout) and in mice with the normal Gsdmd gene (wild-type) using a procedure called cecal ligation and puncture (CLP). The degree of muscular atrophy in the gastrocnemius and tibialis anterior muscles was assessed 72 hours after surgery in the septic mouse model. In addition, the architecture of skeletal muscles, protein expression, and markers associated with pathways leading to muscle atrophy were examined in mice from various groups 72 hours after surgery. The in vitro investigations entailed the use of siRNA to suppress Gsdmd expression in C2C12 cells, followed by stimulation of these cells with lipopolysaccharide (LPS) to evaluate the impact of Gsdmd downregulation on muscle atrophy and the related signaling cascades. RESULTS: This study has demonstrated that the GSDMD protein, known as the "executive" protein of pyroptosis, plays a crucial role in the advancement of skeletal muscle atrophy in septic mice. The expression of N-GSDMD in the skeletal muscle of septic mice was markedly higher compared to the control group. The Gsdmd knockout mice exhibited notable enhancements in survival, muscle strength, and body weight compared to the septic mice. Deletion of the Gsdmd gene reduced muscular wasting in the gastrocnemius and tibialis anterior muscles caused by sepsis. Studies conducted in living organisms (in vivo) and in laboratory conditions (in vitro) have shown that the absence of the Gsdmd gene decreases indicators of muscle loss associated with sepsis by blocking the IL18/AMPK signaling pathway. CONCLUSION: The results of this study demonstrate that the lack of Gsdmd has a beneficial effect on septic skeletal muscle atrophy by reducing the activation of IL18/AMPK and inhibiting the UPS and autophagy pathways. Therefore, our research provides vital insights into the role of pyroptosis in sepsis-related skeletal muscle wasting, which could potentially lead to the development of therapeutic and interventional approaches for preventing septic skeletal muscle atrophy.

Prediction model establishment and validation for enteral nutrition aspiration during hospitalization in patients with acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a disease caused by abnormal activation of pancreatic enzymes and can lead to self-digestion of pancreatic tissues and dysfunction of other organs. Enteral nutrition plays a vital role in the treatment of AP because it can meet the nutritional needs of patients, promote the recovery of intestinal function, and maintain the barrier and immune functions of the intestine. However, the risk of aspiration during enteral nutrition is high; once aspiration occurs, it may cause serious complications, such as aspiration pneumonia, and suffocation, posing a threat to the patient's life. This study aims to establish and validate a prediction model for enteral nutrition aspiration during hospitalization in patients with AP. AIM: To establish and validate a predictive model for enteral nutrition aspiration during hospitalization in patients with AP. METHODS: A retrospective review was conducted on 200 patients with AP admitted to Chengdu Shangjin Nanfu Hospital, West China Hospital of Sichuan University from January 2020 to February 2024. Clinical data were collected from the electronic medical record system. Patients were randomly divided into a validation group (n = 40) and a modeling group (n = 160) in a 1:4 ratio, matched with 200 patients from the same time period. The modeling group was further categorized into an aspiration group (n = 25) and a non-aspiration group (n = 175) based on the occurrence of enteral nutrition aspiration during hospitalization. Univariate and multivariate logistic regression analyses were performed to identify factors influencing enteral nutrition aspiration in patients with AP during hospitalization. A prediction model for enteral nutrition aspiration during hospitalization was constructed, and calibration curves were used for validation. Receiver operating characteristic curve analysis was conducted to evaluate the predictive value of the model. RESULTS: There was no statistically significant difference in general data between the validation and modeling groups (P > 0.05). The comparison of age, gender, body mass index, smoking history, hypertension history, and diabetes history showed no statistically significant difference between the two groups (P > 0.05). However, patient position, consciousness status, nutritional risk, Acute Physiology and Chronic Health Evaluation (APACHE-II) score, and length of nasogastric tube placement showed statistically significant differences (P < 0.05) between the two groups. Multivariate logistic regression analysis showed that patient position, consciousness status, nutritional risk, APACHE-II score, and length of nasogastric tube placement were independent factors influencing enteral nutrition aspiration in patients with AP during hospitalization (P < 0.05). These factors were incorporated into the prediction model, which showed good consistency between the predicted and actual risks, as indicated by calibration curves with slopes close to 1 in the training and validation sets. Receiver operating characteristic analysis revealed an area under the curve (AUC) of 0.926 (95%CI: 0.8889-0.9675) in the training set. The optimal cutoff value is 0.73, with a sensitivity of 88.4 and specificity of 85.2. In the validation set, the AUC of the model for predicting enteral nutrition aspiration in patients with AP patients during hospitalization was 0.902, with a standard error of 0.040 (95%CI: 0.8284-0.9858), and the best cutoff value was 0.73, with a sensitivity of 91.9 and specificity of 81.8. CONCLUSION: A prediction model for enteral nutrition aspiration during hospitalization in patients with AP was established and demonstrated high predictive value. Further clinical application of the model is warranted.

Unraveling the impact of hyperleptinemia on female reproduction: insights from transgenic pig model.

BACKGROUND: Infertility is a growing global health concern affecting millions of couples worldwide. Among several factors, an extreme body weight adversely affects reproductive functions. Leptin is a well-known adipokine that serves as an endocrine signal between adiposity and fertility. However, the exact mechanisms underlying the effects of high leptin level on female reproduction remain unclear. METHODS: Transgenic pigs overexpressing leptin (♀) were produced by backcrossing and screened for leptin overexpression. The growth curve, fat deposition, reproductive performance, apoptosis, serum hormones and cholesterol production, RNA sequencing, and single-nucleus RNA sequencing (snRNA-seq) of the leptin-overexpressing pigs and wild-type group were evaluated. RESULTS: Transgenic pigs overexpressing leptin (♀) were obtained, which exhibited significantly reduced body weight, body size, and back fat thickness. These pigs manifested a late onset of puberty (330 ± 54.3 vs. 155 ± 14.7 days), irregular estrous behavior characterized by increased inter-estrous interval (29.2 ± 0 vs. 21.3 ± 0.7 days), and more number of matings until pregnancy (at least 3 times). This reproductive impairment in leptin pigs was related to hormonal imbalances characterized by increased levels of FSH, LH, prolactin, E2, P4, and TSH, altered steroidogenesis such as increased levels of serum cholesterol esters along with steroidogenic markers (StAR, CYP19A), and ovarian dysfunctions manifested by neutrophilic infiltration and low expression of caspase-3 positive cells in the ovaries. Moreover, bulk RNA sequencing of the ovaries also revealed neutrophilic infiltration followed by upregulation of inflammation-related genes. Furthermore, snRNA-seq reflected that leptin overexpression triggered immune response, suppressed follicle development and luteinization, resulting in metabolic dysfunction and hormone imbalance in the ovary. CONCLUSIONS: Low body weight in leptin overexpressing pigs adversely affects the reproductive performance, causing delayed puberty, irregular estrous cycles, and reduced breeding efficiency. This is linked to metabolic imbalances, an increased immune response, and altered ovarian functions. This study provides a theoretical basis for the complex mechanisms underlying leptin, and infertility by employing leptin-overexpressing female pigs.

Corrigendum: The immunomodulatory mechanism of acupuncture treatment for ischemic stroke: research progress, prospects, and future direction.

[This corrects the article DOI: 10.3389/fimmu.2024.1319863.].

Nanocrystal hydroxyapatite carrying traditional Chinese medicine for osteogenic differentiation.

Developing biomaterials with high osteogenic properties is crucial for achieving rapid bone repair and regeneration. This study focuses on the application of nanocrystal hydroxyapatite (nHAp) as a drug carrier to load Fu Yuan Huo Xue Decoction (FYHXD), a traditional Chinese medicine derived from Angelica sinensis, aiming to achieve improved efficacy in treating bone diseases such as osteoporosis. Through a facile physical adsorption approach, the FTIR result emerges new characteristic absorption peaks in the range of 1200-950 cm-1, proving the successful absorption of FYHXD onto the nHAp with a loading efficiency of 39.76 %. The modified nHAp exhibits a similar shape to the bone-derived hydroxyapatite nanocrystals, and their diameter increases slightly after modification. The drug release assay implies the rapid release of FYHXD in the first 10 h, followed by a continuously slow release within 70 h. The developed nHAp effectively enhances the adhesion, spreading, and proliferation of MC3T3-E1 cells in vitro, and significantly promotes their osteogenic differentiation, as indicated by increased alkaline phosphatase activity. Overall, the biocomposites hold great promise as active ingredients for integration into bone-associated biomaterials, offering the potential to stimulate spontaneous osteogenesis without requiring exogenous osteogenic factors.

FDA Approval Summary: Enfortumab Vedotin Plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma.

On December 15, 2023, the FDA granted traditional approval to enfortumab vedotin-ejfv plus pembrolizumab (EV + Pembro) for patients with locally advanced or metastatic urothelial carcinoma (la/mUC). Substantial evidence of effectiveness was obtained from EV-302/KEYNOTE-A39 (NCT04223856), an open-label, randomized, trial evaluating EV + Pembro versus cisplatin or carboplatin plus gemcitabine (Plat + Gem) in patients with previously untreated la/mUC. A total of 886 patients were randomized (1:1) to receive EV 1.25 mg/kg intravenously on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle for up to 35 cycles, or Plat + Gem for up to 6 cycles. Dual primary endpoints were progression-free survival (PFS) determined by blinded independent central review and overall survival (OS). Median PFS was 12.5 months (95% CI: 10.4, 16.6) in the EV + Pembro arm and 6.3 months (95% CI: 6.2, 6.5) in the Plat + Gem arm (HR 0.450 [95% CI: 0.377, 0.538]; p-value < 0.0001). Median OS was 31.5 months (95% CI: 25.4, NE) in the EV + Pembro arm and 16.1 months (95% CI: 13.9, 18.3) in the Plat + Gem arm (HR 0.468 [95% CI: 0.376, 0.582]; p-value < 0.0001). The safety profile of EV + pembrolizumab was similar to that observed in EV-103/KEYNOTE-869 in cisplatin-ineligible patients with la/mUC. This article summarizes the data and the FDA thought process supporting traditional approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by FDA.

Artificial Intelligence Measurement of Preoperative Radiographs in Adolescent Idiopathic Scoliosis Based on Multiple-View Semantic Segmentation.

STUDY DESIGN: Cross-sectional study. OBJECTIVES: Imaging classification of adolescent idiopathic scoliosis (AIS) is directly related to the surgical strategy, but the artificial classification is complex and depends on doctors' experience. This study investigated deep learning-based automated classification methods (DL group) for AIS and validated the consistency of machine classification and manual classification (M group). METHODS: A total of 506 cases (81 males and 425 females) and 1812 AIS full spine images in the anteroposterior (AP), lateral (LAT), left bending (LB) and right bending (RB) positions were retrospectively used for training. The mean age was 13.6 ± 1.8. The mean maximum Cobb angle was 46.8 ± 12.0. U-Net semantic segmentation neural network technology and deep learning methods were used to automatically segment and establish the alignment relationship between multiple views of the spine, and to extract spinal features such as the Cobb angle. The type of each test case was automatically calculated according to Lenke's rule. An additional 107 cases of adolescent idiopathic scoliosis imaging were prospectively used for testing. The consistency of the DL group and M group was compared. RESULTS: Automatic vertebral body segmentation and recognition, multi-view alignment of the spine and automatic Cobb angle measurement were implemented. Compare to the M group, the consistency of the DL group was significantly higher in 3 aspects: type of lateral convexity (0.989 vs 0.566), lumbar curvature modifier (0.932 vs 0.738), and sagittal plane modifier (0.987 vs 0.522). CONCLUSIONS: Deep learning enables automated Cobb angle measurement and automated Lenke classification of idiopathic scoliosis whole spine radiographs with higher consistency than manual measurement classification.

Improved YOLOv8 Algorithm for Water Surface Object Detection.

To address the issues of decreased detection accuracy, false detections, and missed detections caused by scale differences between near and distant targets and environmental factors (such as lighting and water waves) in surface target detection tasks for uncrewed vessels, the YOLOv8-MSS algorithm is proposed to be used to optimize the detection of water surface targets. By adding a small target detection head, the model becomes more sensitive and accurate in recognizing small targets. To reduce noise interference caused by complex water surface environments during the downsampling process in the backbone network, C2f_MLCA is used to enhance the robustness and stability of the model. The lightweight model SENetV2 is employed in the neck component to improve the model's performance in detecting small targets and its anti-interference capability. The SIoU loss function enhances detection accuracy and bounding box regression precision through shape awareness and geometric information integration. Experiments on the publicly available dataset FloW-Img show that the improved algorithm achieves an mAP@0.5 of 87.9% and an mAP@0.5:0.95 of 47.6%, which are improvements of 5% and 2.6%, respectively, compared to the original model.

Rapid photothermal assay for ultrasensitive point-of-care detection of tumor markers based on a filter membrane.

An ultrasensitive photothermal assay was designed for point-of-care testing (POCT) of tumor markers based on a filter membrane. Firstly, Cu2-xSe was successfully encapsulated in liposome spheres with biotin on the surface and connected to carcinoembryonic antigen (CEA) aptamer with 3'end modified biotin by streptavidin. Secondly, the CEA antibody was successfully modified on the surface of the nitrocellulose membrane through simple incubation. Finally, the assay process was completed using a disposable syringe, and the temperature was recorded using a handheld infrared temperature detector. In the range 0-50 ng mL-1, the temperature change of the nitrocellulose membrane has a strong linear relationship with CEA concentration, and the detection limit is 0.097 ng mL-1. It is worth noting that the entire testing process can be easily performed in 10 min, much shorter than traditional clinical methods. In addition, this method was successfully applied to the quantitative determination of CEA levels in human serum samples with a recovery of 96.2-103.3%. This rapid assay can be performed by "one suction and one push" through a disposable syringe, which is simple to operate, and the excellent sensitivity reveals the great potential of the proposed strategy in the POCT of tumor biomarkers.

Exploring the impact of women-specific reproductive factors on phenotypic aging and the role of life's essential 8.

BACKGROUND: Aging is an inevitable biological process. Accelerated aging renders adults more susceptible to chronic diseases and increases their mortality rates. Previous studies have reported the relationship between lifestyle factors and phenotypic aging. However, the relationship between intrinsic factors, such as reproductive factors, and phenotypic aging remains unclear. METHODS: This study utilized data from the National Health and Nutrition Examination Survey (NHANES), spanning from 1999 to 2010 and 2015-2018, with 14,736 adult women. Random forest imputation was used to handle missing covariate values in the final cohort. Weighted linear regression was utilized to analyze the relationship between women-specific reproductive factors and PhenoAgeAccel. Considering the potential impact of menopausal status on the results, additional analyses were conducted on premenopausal and postmenopausal participants. Additionally, the Life's Essential 8 (LE8) was used to investigate the impact of healthy lifestyle and other factors on the relationship between women-specific reproductive factors and PhenoAgeAccel. Stratified analyses were conducted based on significant interaction p-values. RESULTS: In the fully adjusted models, delayed menarche and gynecological surgery were associated with increased PhenoAgeAccel, whereas pregnancy history were associated with a decrease. Additionally, early or late ages of menopause, first live birth, and last live birth can all negatively impact PhenoAgeAccel. The relationship between women-specific reproductive factors and PhenoAgeAccel differs between premenopausal and postmenopausal women. High LE8 scores positively impacted the relationship between certain reproductive factors (age at menarche, age at menopause, age at first live birth, and age at last live birth) and phenotypic age acceleration. Stratified analysis showed significant interactions for the following variables: BMI with age at menarche, pregnancy history, and age at menopause; ethnicity with age at menopause, age at first live birth, and parity; smoking status with use of contraceptive pills and gynecologic surgery; hypertension with use of contraceptive pills, pregnancy history, and age at menopause. CONCLUSION: Delayed menarche, gynecological surgery, and early or late ages of menopause, first live birth, and last live birth are associated with accelerated phenotypic aging. High LE8 score may alleviate the adverse effects of reproductive factors on phenotypic aging.

[Spatio-temporal Heterogeneity of Factors Influencing Transportation Carbon Emissions in Provinces Along the Belt and Road].

The administrative units of 17 provinces （autonomous regions and municipalities directly under the Central Government） along the "Belt and Road" were selected as basic spatial units to calculate the provincial traffic carbon emissions along the "Belt and Road" from 2000 to 2021. On the basis of analyzing the spatial and temporal characteristics of traffic carbon emissions by using the spatial autocorrelation method, the spatial and temporal heterogeneity of influencing factors of traffic carbon emissions was explored by combining a fixed-effect regression model and geographic detector. The results show that： ① The provincial traffic carbon emissions along the "Belt and Road" had significant spatial positive correlation, and the overall trend was upward. Additionally, the cluster evolution of high and low values of traffic carbon emissions presented the characteristics of polarization in space. The high value cluster area was mainly distributed in the open leading area, and the low value cluster area was mainly distributed in the core area of the silk road. ② Opening-up level and vehicle ownership were the positive driving factors of carbon emissions from transportation, whereas energy intensity, transportation structure, industry development scale, and government intervention were the negative driving factors. ③ Energy intensity and transportation structure were the main driving factors for the spatial variation of transportation carbon emissions, and most of them would produce nonlinear enhancement when they were spatially superimposed with other factors, that is, there was strong synergy among driving factors. The results showed that the provincial traffic carbon emissions along the "Belt and Road" were affected by the surrounding areas, the influence degree was increasing, and there was synergy between the key driving factors of traffic carbon emissions. Therefore, it is suggested that the provinces along the "Belt and Road" should fully consider the spatial and temporal heterogeneity of traffic carbon emission influencing factors and formulate differentiated traffic carbon emission reduction policies.

Solution-plasma interaction for synthesizing highly active Pt-Ni alloy oxygen reduction nanocatalysts for PEMFCs.

A highly active PtNi-alloy catalyst (p-PtNi/KB) is synthesized using solution-plasma interaction. The plasma effect results in a substantial increase of active sites on the support surface. This facilitates the alloying and functionalization of supports, enabling achievement of enhanced catalytic activity and effective resolution of cost-related challenges in fuel cells.

Epimedin A inhibits the PI3K/AKT/NF-κB signalling axis and osteoclast differentiation by negatively regulating TRAF6 expression.

BACKGROUND: Epimedin A (EA) has been shown to suppress extensive osteoclastogenesis and bone resorption, but the effects of EA remain incompletely understood. The aim of our study was to investigate the effects of EA on osteoclastogenesis and bone resorption to explore the corresponding signalling pathways. METHODS: Rats were randomly assigned to the sham operation or ovariectomy group, and alendronate was used for the positive control group. The therapeutic effect of EA on osteoporosis was systematically analysed by measuring bone mineral density and bone biomechanical properties. In vitro, RAW264.7 cells were treated with receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) to induce osteoclast differentiation. Cell viability assays, tartrate-resistant acid phosphatase (TRAP) staining, and immunofluorescence were used to elucidate the effects of EA on osteoclastogenesis. In addition, the expression of bone differentiation-related proteins or genes was evaluated using Western blot analysis or quantitative polymerase chain reaction (PCR), respectively. RESULTS: After 3 months of oral EA intervention, ovariectomized rats exhibited increased bone density, relative bone volume, trabecular thickness, and trabecular number, as well as reduced trabecular separation. EA dose-dependently normalized bone density and trabecular microarchitecture in the ovariectomized rats. Additionally, EA inhibited the expression of TRAP and NFATc1 in the ovariectomized rats. Moreover, the in vitro results indicated that EA inhibits osteoclast differentiation by suppressing the TRAF6/PI3K/AKT/NF-κB pathway. Further studies revealed that the effect on osteoclast differentiation, which was originally inhibited by EA, was reversed when the TRAF6 gene was overexpressed. CONCLUSIONS: The findings indicated that EA can negatively regulate osteoclastogenesis by inhibiting the TRAF6/PI3K/AKT/NF-κB axis and that ameliorating ovariectomy-induced osteoporosis in rats with EA may be a promising potential therapeutic strategy for the treatment of osteoporosis.

Variation characteristics and clinical significance of TP53 in patients with myeloid neoplasms.

Objectives: MDS and AML characterized by TP53 variations have a poor prognosis in general. However, specifically, differences in prognosis have also been observed in patients with different TP53 variants and VAFs.Methods: Here, we retrospectively analyzed datasets of patients with MDS, MPN, and AML who underwent targeted DNA sequencing from February 2018 to December 2023, and patients with reportable TP53 variations were screened. Demographic data and clinical data were collected, and the relationship between TP53 alterations and patient prognosis (AML/MDS) was analyzed using the cBioPortal and Kaplan-Meier Plotter databases. The relationship between the VAFs of TP53 variations and prognoses was analyzed using data from the present study.Results: Sixty-two variants of TP53 were identified in 58 patients. We mainly identified single mutations (79.31%, 46/58), followed by double (17.24%, 10/58) and triple (3.45%, 2/58) mutations. The variations were mainly enriched in exon4-exon8 of TP53. Missense (72.58%, 45/62) mutations were the main type of variations, followed by splice-site (9.68%, 6/62), nonsense (9.68%, 6/62), frameshift (6.45%, 4/62), and indel (1.61%, 1/62) mutations. In this study, p.Arg175His and p.Arg273His were high-frequency TP53 mutations, and DNMT3A and TET2 were commonly co-mutated genes in the three types of myeloid neoplasms; However, we reported some new TP53 variants in MPN that have not been found in the public database. Moreover, MDS or AML characterized by altered TP53 had a shorter OS than patients in the unaltered group (P<0.01), low TP53 mRNA levels were associated with shorter OS in patients with AML (P<0.01). Data from our center further found higher VAF (≥10%) associated with shorter OS in patients with MDS (median 2.75 vs. 24 months) (P<0.01).Conclusion: TP53 mutations are mainly enriched in exon4-exon8, are missense and single mutations in myeloid neoplasms, and are associated with poor prognosis of MDS/AML, and higher VAF (≥10%) of TP53 mutations associated with a shorter OS in patients with MDS.

Effects of personalized music listening on post-stroke cognitive impairment: A randomized controlled trial.

BACKGROUND AND PURPOSE: Previous studies have suggested that music listening has the potential to positively affect cognitive functions and mood in individuals with post-stroke cognitive impairment (PSCI), with a preference for self-selected music likely to yield better outcomes. However, there is insufficient clinical evidence to suggest the use of music listening in routine rehabilitation care to treat PSCI. This randomized control trial (RCT) aims to investigate the effects of personalized music listening on mood improvement, activities of daily living (ADLs), and cognitive functions in individuals with PSCI. MATERIALS AND METHODS: A total of 34 patients with PSCI were randomly assigned to either the music group or the control group. Patients in the music group underwent a three-month personalized music-listening intervention. The intervention involved listening to a personalized playlist tailored to each individual's cultural, ethnic, and social background, life experiences, and personal music preferences. In contrast, the control group patients listened to white noise as a placebo. Cognitive function, neurological function, mood, and ADLs were assessed. RESULTS: After three months of treatment, the music group showed significantly higher Montreal Cognitive Assessment (MoCA) scores compared to the control group (p=0.027), particularly in the domains of delayed recall (p=0.019) and orientation (p=0.023). Moreover, the music group demonstrated significantly better scores in National Institutes of Health Stroke Scale (NIHSS) (p=0.008), Barthel Index (BI) (p=0.019), and Zarit Caregiver Burden Interview (ZBI) (p=0.008) compared to the control group. No effects were found on mood as measured by the Hamilton Anxiety Rating Scale (HAMA) and the Hamilton Depression Rating Scale (HAMD). CONCLUSION: Personalized music listening promotes the recovery of cognitive and neurological functions, improves ADLs, and reduces caregiver burden in patients with PSCI.

Adjuvant camrelizumab plus apatinib in resected hepatocellular carcinoma with microvascular invasion: a multi-center real world study.

Background: Hepatocellular carcinoma (HCC) treatment currently lacks adjuvant therapy with a high level of supporting evidence to reduce recurrence after hepatectomy. This study aimed to assess the safety and efficacy of camrelizumab plus apatinib in the adjuvant therapy of patients with HCC with microvascular invasion (MVI). Methods: Data were retrospectively collected on consecutive patients with HCC who underwent radical resection and were diagnosed with MVI-positive tumors between October 2019 and June 2022 at four centers. The association between adjuvant therapy and prognosis [recurrence-free survival (RFS), overall survival (OS)] was evaluated by propensity score matching (PSM), the log-rank test, Cox regression analysis, and subgroup analysis. Furthermore, grade 3 or 4 treatment-related adverse events (TRAEs) of adjuvant therapy were reported. Results: Among the 111 patients in the adjuvant therapy group and 276 patients in the observation group at enrolment, there were 99 and 172 in the adjuvant therapy and observation groups after PSM, respectively. RFS was better in the adjuvant therapy group [hazard ratio (HR) 0.52; 95% confidence interval (CI): 0.39 to 0.69; P<0.001], whereas OS was not (HR 0.62; 95% CI: 0.39 to 0.99; P=0.079). These results were confirmed after PSM. Subgroup analyses were generally consistent in favour of adjuvant camrelizumab plus apatinib with better RFS. Grade 3 or 4 TRAEs accounted for 20.7% during adjuvant therapy; the most common TRAEs included hypertension and proteinuria. Conclusions: Postoperative adjuvant camrelizumab plus apatinib significantly improved the RFS benefits with acceptable toxicities in patients with HCC with MVI.

Vinpocetine alleviates the abdominal aortic aneurysm progression via VSMCs SIRT1-p21 signaling pathway.

Abdominal aortic aneurysm (AAA) is a degenerative disease that caused mortality in people aged >65. Senescence plays a critical role in AAA pathogenesis. Advances in AAA repair techniques have occurred, but a remaining priority is therapies to limit AAA growth and rupture. Our Previous study found cyclic nucleotide phosphodiesterase 1C (PDE1C) exacerbate AAA through aggravate vascular smooth muscle cells (VSMCs) senescence by downregulating Sirtuin1 (SIRT1) expression and activity. Vinpocetine as a selective inhibitor of PDE1 and a clinical medication for cerebral vasodilation, it is unclear whether vinpocetine can rely on SIRT1 to alleviate AAA. This study showed that pre-treatment with vinpocetine remarkably prevented aneurysmal dilation and reduced aortic rupture in elastase-induced AAA mice. In addition, the elastin degradation, MMP (matrix metalloproteinase) activity, macrophage infiltration, ROS production, collagen fibers remodeling, and VSMCs senescence were decreased in AAA treated with vinpocetine. While these effects were unable to exert in VSMCs-specific SIRT1 knockout AAA mice. Accordingly, we revealed that vinpocetine suppressed migration, proliferation, and senescence in VSMCs. Moreover, vinpocetine reduced SIRT1 degradation by inhibiting lysosome-mediated autophagy. In conclusion, this study indicated that vinpocetine may be as a potential drug for therapy AAA through alleviate VSMCs senescence via the SIRT1-dependent pathway.

Production of Four-Gene (GTKO/hCD55/hTBM/hCD39)-Edited Donor Pigs and Kidney Xenotransplantation.

BACKGROUND: The number of multigene-modified donor pigs for xenotransplantation is increasing with the advent of gene-editing technologies. However, it remains unclear which gene combination is suitable for specific organ transplantation. METHODS: In this study, we utilized CRISPR/Cas9 gene editing technology, piggyBac transposon system, and somatic cell cloning to construct GTKO/hCD55/hTBM/hCD39 four-gene-edited cloned (GEC) pigs and performed kidney transplantation from pig to rhesus monkey to evaluate the effectiveness of these GEC pigs. RESULTS: First, 107 cell colonies were obtained through drug selection, of which seven were 4-GE colonies. Two colonies were selected for somatic cell nuclear transfer (SCNT), resulting in seven fetuses, of which four were GGTA1 biallelic knockout. Out of these four, two fetuses had higher expression of hCD55, hTBM, and hCD39. Therefore, these two fetuses were selected for two consecutive rounds of cloning, resulting in 97 live piglets. After phenotype identification, the GGTA1 gene of these pigs was inactivated, and hCD55, hTBM, and hCD39 were expressed in cells and multiple tissues. Furthermore, the numbers of monkey IgM and IgG binding to the peripheral blood mononuclear cells (PBMCs) of the 4-GEC pigs were markedly reduced. Moreover, 4-GEC porcine PBMCs had greater survival rates than those from wild-type pigs through complement-mediated cytolysis assays. In pig-to-monkey kidney xenotransplantation, the kidney xenograft successfully survived for 11 days. All physiological and biochemical indicators were normal, and no hyperacute rejection or coagulation abnormalities were found after transplantation. CONCLUSION: These results indicate that the GTKO/hCD55/hTBM/hCD39 four-gene modification effectively alleviates immune rejection, and the pig kidney can functionally support the recipient monkey's life.

Lateral pelvic lymph nodes dissection of rectal neuroendocrine neoplasms: A prospective case-series and literature review.

BACKGROUND: Rectal neuroendocrine neoplasms are relatively rare. Patients with rectal neuroendocrine neoplasms undergoing radical surgery have a higher rate of lymph node metastases. Robust evidence on the status of lateral pelvic lymph node metastases and the role of lateral pelvic lymph node dissection in those patients is lacking. This case-series study aimed to explore and address these issues. METHODS: This single-center, prospective case series consecutively enrolled patients with biopsy-proven rectal neuroendocrine neoplasms in a tertiary referral hospital between June 2022 and January 2024. All eligible patients underwent laparoscopic total mesorectal excision surgery and bilateral lateral pelvic lymph node dissection under general anesthesia. The clinicopathologic features, surgical outcomes, and postoperative complications were presented. The last follow-up was conducted in March 2024. RESULTS: A total of 11 patients with rectal neuroendocrine neoplasms-3 female and 8 male-were enrolled. The average age was 60.0 years (range, 53.5-65.5 years), and the median tumor size was 2.0 cm (range, 1.6-2.5 cm). Tumors invaded the muscularis propria in 7 patients. There were 3 cases of neuroendocrine tumor G1, 6 cases of neuroendocrine tumor G2, and 2 cases of neuroendocrine carcinoma. Among these patients, 11 (100.0%) had lymph node metastases, and 6 (54.5%) had lateral pelvic lymph node metastases. In addition, in 2 patients, only lateral pelvic lymph node metastases were observed, without involvement of the mesenteric lymph nodes. Five patients had tumors located on the left wall of the rectum, and only left-sided lateral pelvic lymph node metastases were observed. The other patient had both sides of lateral pelvic lymph node metastases due to circumferential growth of the tumor around the rectum. Anal preservation was achieved in all patients. The median operating time was 235.0 minutes (range, 210.5-335.5 minutes), and the median estimated blood loss was 50.0 mL (range, 45.0-75.0 mL). Two patients experienced postoperative dysuria and recovered spontaneously within 2-4 months after surgery. CONCLUSION: On the basis of a prospective case series, we demonstrate, for the first time, the lateral pelvic lymph node metastasis status in patients with rectal neuroendocrine neoplasms requiring radical total mesorectal excision surgery. Simultaneous bilateral lateral pelvic lymph node dissection may be a feasible and beneficial procedure for preventing local recurrence in these patients due to the lack of definitive neoadjuvant or adjuvant therapy options.