ABO and Rhesus blood groups and multiple health outcomes: an umbrella review of systematic reviews with meta-analyses of observational studies.

BACKGROUND: Numerous studies have been conducted to investigate the relationship between ABO and Rhesus (Rh) blood groups and various health outcomes. However, a comprehensive evaluation of the robustness of these associations is still lacking. METHODS: We searched PubMed, Web of Science, Embase, Scopus, Cochrane, and several regional databases from their inception until Feb 16, 2024, with the aim of identifying systematic reviews with meta-analyses of observational studies exploring associations between ABO and Rh blood groups and diverse health outcomes. For each association, we calculated the summary effect sizes, corresponding 95% confidence intervals, 95% prediction interval, heterogeneity, small-study effect, and evaluation of excess significance bias. The evidence was evaluated on a grading scale that ranged from convincing (Class I) to weak (Class IV). We assessed the certainty of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation criteria (GRADE). We also evaluated the methodological quality of included studies using the A Measurement Tool to Assess Systematic Reviews (AMSTAR). AMSTAR contains 11 items, which were scored as high (8-11), moderate (4-7), and low (0-3) quality. We have gotten the registration for protocol on the PROSPERO database (CRD42023409547). RESULTS: The current umbrella review included 51 systematic reviews with meta-analysis articles with 270 associations. We re-calculated each association and found only one convincing evidence (Class I) for an association between blood group B and type 2 diabetes mellitus risk compared with the non-B blood group. It had a summary odds ratio of 1.28 (95% confidence interval: 1.17, 1.40), was supported by 6870 cases with small heterogeneity (I2 = 13%) and 95% prediction intervals excluding the null value, and without hints of small-study effects (P for Egger's test > 0.10, but the largest study effect was not more conservative than the summary effect size) or excess of significance (P < 0.10, but the value of observed less than expected). And the article was demonstrated with high methodological quality using AMSTAR (score = 9). According to AMSTAR, 18, 32, and 11 studies were categorized as high, moderate, and low quality, respectively. Nine statistically significant associations reached moderate quality based on GRADE. CONCLUSIONS: Our findings suggest a potential relationship between ABO and Rh blood groups and adverse health outcomes. Particularly the association between blood group B and type 2 diabetes mellitus risk.

Effect of CTLA-4 Inhibition on Inflammation and Apoptosis After Spinal Cord Injury.

Spinal cord injury (SCI) encompasses various pathological processes, notably neuroinflammation and apoptosis, both of which play significant roles. CTLA-4, a well-known immune molecule that suppresses T cell-mediated immune responses, is a key area of research and a focal point for targeted therapy development in treating tumors and autoimmune disorders. Despite its prominence, the impact of CTLA-4 inhibition on inflammation and apoptosis subsequent to SCI remains unexplored. This study aimed to investigate the influence of CTLA-4 on SCI. A weight-drop technique was used to establish a rat model of SCI. To examine the safeguarding effect of CTLA-4 on the restoration of motor function in rats with SCI, the Basso-Beattie-Bresnahan (BBB) scale and inclined plane test were employed to assess locomotion. Neuronal degeneration and apoptosis were assessed using terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) and Fluoro-Jade B labeling, respectively, and the activity of microglial cells was examined by immunofluorescence. To evaluate the impact of CTLA4 on SCI, the levels of inflammatory markers were measured. After treatment with the CTLA-4 inhibitor ipilimumab, the rats showed worse neurological impairment and more severe neuroinflammation after SCI. Furthermore, the combination therapy with ipilimumab and durvalumab after SCI had more pronounced effects than treatment with either inhibitor alone. These findings indicate that CTLA-4 contributes to neuroinflammation and apoptosis after SCI, presenting a promising new therapeutic target for this traumatic condition.

Dapagliflozin Suppresses Isoprenaline-Induced Cardiac Hypertrophy Through Inhibition of Mitochondrial Fission.

ABSTRACT: Dapagliflozin (DAPA) is a novel oral hypoglycemic agent, and there is increasing evidence that DAPA has a protective effect against cardiovascular disease. The study aimed to investigate how DAPA inhibits cardiac hypertrophy and explore its potential mechanisms. By continuously infusing isoprenaline (ISO) for 2 weeks using a subcutaneous osmotic pump, a cardiac hypertrophic model was established in male C57BL/6 mice. On day 14 after surgery, echocardiography showed that left ventricle mass (LV mass), interventricular septum, left ventricle posterior wall diastole, and left ventricular posterior wall systole were significantly increased, and ejection fraction was decreased compared with control mice. Masson and Wheat Germ Agglutinin staining indicated enhanced myocardial fibrosis and cell morphology compared with control mice. Importantly, these effects were inhibited by DAPA treatment in ISO-induced mice. In H9c2 cells and neonatal rat cardiomyocytes, we found that mitochondrial fragmentation and mitochondrial oxidative stress were significantly augmented in the ISO-induced group. However, DAPA rescued the cardiac hypertrophy in ISO-induced H9c2 cells and neonatal rat cardiomyocytes. Mechanistically, we found that DAPA restored the PIM1 activity in ISO-induced H9c2 cells and subsequent increase in dynamin-associated protein 1 (Drp1) phosphorylation at S616 and decrease in Drp1 phosphorylation at S637 in ISO-induced cells. We found that DAPA mitigated ISO-induced cardiac hypertrophy by suppressing Drp1-mediated mitochondrial fission in a PIM1-dependent fashion.

Characterization of AST-001 non-clinical pharmacokinetics: A novel selective AKR1C3-activated prodrug in mice, rats, and cynomolgus monkeys.

AST-001 is a chemically synthesized inactive nitrogen mustard prodrug that is selectively cleaved to a cytotoxic aziridine (AST-2660) via aldo-keto reductase family 1 member C3 (AKR1C3). The purpose of this study was to investigate the pharmacokinetics and tissue distribution of the prodrug, AST-001, and its active metabolite, AST-2660, in mice, rats, and monkeys. After single and once daily intravenous bolus doses of 1.5, 4.5, and 13.5 mg/kg AST-001 to Sprague-Dawley rats and once daily 1 h intravenous infusions of 0.5, 1.5, and 4.5 mg/kg AST-001 to cynomolgus monkeys, AST-001 exhibited dose-dependent pharmacokinetics and reached peak plasma levels at the end of the infusion. No significant accumulation and gender differences were observed after 7 days of repeated dosing. In rats, the half-life of AST-001 was dose independent and ranged from 4.89 to 5.75 h. In cynomolgus monkeys, the half-life of AST-001 was from 1.66 to 5.56 h and increased with dose. In tissue distribution studies conducted in Sprague-Dawley rats and in liver cancer PDX models in female athymic nude mice implanted with LI6643 or LI6280 HepG2-GFP tumor fragments, AST-001 was extensively distributed to selected tissues. Following a single intravenous dose, AST-001 was not excreted primarily as the prodrug, AST-001 or the metabolite AST-2660 in the urine, feces, and bile. A comprehensive analysis of the preclinical data and inter-species allometric scaling were used to estimate the pharmacokinetic parameters of AST-001 in humans and led to the recommendation of a starting dose of 5 mg/m2 in the first-in-human dose escalation study.

Spin-Steered Photosynthesis of H2O2 in Magnetic Single-Atom Modified Covalent Triazine Frameworks: A Density Functional Theory Study.

Covalent Organic Frameworks (COFs) demonstrate promising potential in the photocatalytic synthesis of H2O2 owing to favorable light absorption, superior charge separation, and considerable surface area. However, the efficiency of H2O2 photosynthesis is impeded by insufficient O2 adsorption sites and a high reaction barrier. In this work, various metal single atoms (Fe, Co, Ni) are introduced onto covalent triazine frameworks (CTFs) with N-N coordination sites to significantly enhance O2 adsorption and optimize H2O2 synthesis. Computational findings suggest that the presence of Fe, Co, and Ni not only enhances O2 adsorption but also exerts an influence on the reaction pathway of H2O2. Significantly, Fe exhibits a distinct advantage in modulating O2 adsorption through its unique electron spin state when compared to Co and Ni, as confirmed by crystal orbital Hamilton population (COHP) analysis. Additionally, this integration of metal atoms also improves light absorption and charge separation in CTFs. The study provides strategic insight into elevating H2O2 production by incorporating tailored metal single atoms into COFs.

Angiotensin-(1-9) prevents angiotensin II-induced endothelial apoptosis through CNPY2/PERK pathway.

Endothelial apoptosis caused by activation of renin-angiotensin system (RAS) plays a vital part in the occurrence and progress of hypertension. Angiotensin-(1-9) (Ang-(1-9)) is a peptide of the counter-regulatory non-classical RAS with anti-hypertensive effects in vascular endothelial cells (ECs). However, the mechanism of action remains unclear. Considering that the endothelial apoptosis was closely related to endoplasmic reticulum stress (ERS) and mitochondrial function. Herein, we aimed to elucidate the effects of Ang-(1-9) on endothelial apoptosis and the underlying molecular mechanism in angiotensin II (Ang II) induced hypertension. In human umbilical vascular endothelial cells (HUVECs), we observed Ang-(1-9) inhibited Ang II-induced ERS associated endothelial apoptosis. Mechanically, Ang-(1-9) inhibited endothelial apoptosis by blocking CNPY2/PERK mediated CaMKII/Drp1-dependent mitochondrial fission and eIF2α/CHOP signal. Consistent with above effects in HUVECs, in Ang II-induced hypertensive mice, we found administration of exogenous Ang-(1-9) attenuated endothelial apoptosis and arterial blood pressure, which were mediated by CNPY2/PERK signaling pathway. Our study indicated Ang-(1-9) inhibited Ang II-induced hypertension through CNPY2/PERK pathway. These findings may provide new insights for prevention and treatment of hypertension in future.

Controllable Architecture of ZnO/FeNi Composites Derived from Trimetallic ZnFeNi Layered Double Hydroxides for High-Performance Electromagnetic Wave Absorbers.

The optimization design of micro-structure and composition is an important strategy to obtain high-performance metal-based electromagnetic (EM) wave absorption materials. In this work, ZnO/FeNi composites derived from ZnFeNi layered double hydroxides are prepared by a one-step hydrothermal method and subsequent pyrolysis process, and can be employed as an effective alternative for high-performance EM wave absorber. A series of ZnO/FeNi composites with different structures are obtained by varying the molar ratios of Zn2+ /Fe3+ /Ni2+ , and the ZnO/FeNi composites with a Zn2+ /Fe3+ /Ni2+ molar ratio of 6:1:3 show a hierarchical flower-like structure. Owing to the strong synergistic loss mechanism of dielectric-magnetic components and favorable structural features, this hierarchical flower-like ZnO/FeNi sample supplies the optimal EM wave absorption performance with the highest reflection loss of -52.08 dB and the widest effective absorption bandwidth of 6.56 GHz. The EM simulation further demonstrates that impedance matching plays a determining role in EM wave absorption performance. This work provides a new way for the fabrication of a high-performance metal-based EM wave absorber.

A high-dimensional mediation model for a neuroimaging mediator: Integrating clinical, neuroimaging, and neurocognitive data to mitigate late effects in pediatric cancer.

Pediatric cancer treatment, especially for brain tumors, can have profound and complicated late effects. With the survival rates increasing because of improved detection and treatment, a more comprehensive understanding of the impact of current treatments on neurocognitive function and brain structure is critically needed. A frontline medulloblastoma clinical trial (SJMB03) has collected data, including treatment, clinical, neuroimaging, and cognitive variables. Advanced methods for modeling and integrating these data are critically needed to understand the mediation pathway from the treatment through brain structure to neurocognitive outcomes. We propose an integrative Bayesian mediation analysis approach to model jointly a treatment exposure, a high-dimensional structural neuroimaging mediator, and a neurocognitive outcome and to uncover the mediation pathway. The high-dimensional imaging-related coefficients are modeled via a binary Ising-Gaussian Markov random field prior (BI-GMRF), addressing the sparsity, spatial dependency, and smoothness and increasing the power to detect brain regions with mediation effects. Numerical simulations demonstrate the estimation accuracy, power, and robustness. For the SJMB03 study, the BI-GMRF method has identified white matter microstructure that is damaged by cancer-directed treatment and impacts late neurocognitive outcomes. The results provide guidance on improving treatment planning to minimize long-term cognitive sequela for pediatric brain tumor patients.

Sarcopenia is associated with non-motor symptoms in Han Chinese patients with Parkinson's Disease: a cross-sectional study.

BACKGROUND: Sarcopenia is commonly seen in the older adults and increases in incidence with age, also in Parkinson's disease (PD). Although research has indicated that the development of sarcopenia in patients with PD may be related to both motor symptoms and non-motor symptoms (NMS), the precise relationship between the two conditions remains unclear. Therefore, we aimed to investigate the incidence of sarcopenia in patients with PD and its association with NMS. METHODS: The study included 123 patients with PD and 38 age- and sex-matched healthy controls (HC). All participants were evaluated for sarcopenia using the 2019 Asian Sarcopenia Diagnostic Criteria, and patients with PD underwent standard assessments of motor symptoms and NMS. Multiple logistic regression and receiver operating characteristic (ROC) curve analyses were used to examine the association between sarcopenia and NMS in patients with PD. RESULTS: The incidence of sarcopenia was significantly higher in patients with PD than in HC (26.8% vs. 10.4%, p = 0.046). Multiple logistic regression analysis revealed that poorer sleep quality (odds ratio [OR]: 1.245; 95% confidence interval [CI]: 1.011-1.533; p = 0.040) and fatigue (OR: 1.085, 95% CI: 1.006-1.170, p = 0.034) were independently associated with sarcopenia. ROC analysis indicated that the optimal cut-off value for Pittsburgh Sleep Quality Index (PSQI) scores was 10, with 72.7% sensitivity and 74.4% specificity (area under the curve [AUC] = 0.776, 95% CI: 0.683-0.868, p < 0.001). The optimal cut-off value for Fatigue Severity Scale (FSS) scores was 39, with 87% sensitivity and 50% specificity (AUC = 0.725, 95% CI: 0.629 -0.820, p < 0.001). Joint use of FSS and PSQI scores increased the predictive value for sarcopenia(AUC = 0.804, 95% CI: 0.724-0.885, p < 0.001). CONCLUSION: Patients with PD are more susceptible to sarcopenia than healthy older adults, and fatigue and poorer sleep are positively associated with sarcopenia. Further longitudinal studies are needed to clarify the causal relationships.

Horsfielenigans A and B, Two Rearranged Lignans with Anti-Inflammatory Effects from Horsfieldia kingii.

Seven lignans were isolated from 70 % aqueous acetone extracts of the twigs and leaves of Horsfieldia kingii. Among these, new compounds 1-3 were identified by spectroscopic techniques, with horsfielenigans A and B (1 and 2) being particularly noteworthy for their rare ß-benzylnaphthalene skeleton, where compound 1 contains an oxabicyclo[3,2,1]octane moiety. In vitro evaluation of bioactivity against nitric oxide (NO) production in LPS-activated RAW264.7 macrophages revealed inhibitory effects by 1 (IC50 =7.3 µM) and 2 (IC50 =9.7 µM).

Hierarchical Pt-In Nanowires for Efficient Methanol Oxidation Electrocatalysis.

Direct methanol fuel cells (DMFC) have attracted increasing research interest recently; however, their output performance is severely hindered by the sluggish kinetics of the methanol oxidation reaction (MOR) at the anode. Herein, unique hierarchical Pt-In NWs with uneven surface and abundant high-index facets are developed as efficient MOR electrocatalysts in acidic electrolytes. The developed hierarchical Pt89In11 NWs exhibit high MOR mass activity and specific activity of 1.42 A mgPt-1 and 6.2 mA cm-2, which are 5.2 and 14.4 times those of Pt/C, respectively, outperforming most of the reported MORs. In chronoamperometry tests, the hierarchical Pt89In11 NWs demonstrate a longer half-life time than Pt/C, suggesting the better CO tolerance of Pt89In11 NWs. After stability, the MOR activity can be recovered by cycling. XPS, CV measurement and CO stripping voltammetry measurements demonstrate that the outstanding catalytic activity may be attributed to the facile removal of CO due to the presence of In site-adsorbing hydroxyl species.

Identification and validation of TNFRSF4 as a high-profile biomarker for prognosis and immunomodulation in endometrial carcinoma.

BACKGROUND: The interaction between tumor microenvironment (TME) and tumors offers various targets in mounting anti-tumor immunotherapies. However, the prognostic biomarkers in endometrial carcinoma (EC) are still limited. Here, we aimed to analyze the TME features and identify novel prognostic biomarkers for EC. METHODS: ESTIMATE, CIBERSORT, protein-protein interaction (PPI) network, univariate and multivariate Cox regression, and functional enrichment analysis were performed to identify immune- and survival-related hub genes as well as possible molecular mechanisms. The limma package and deconvolution algorithm were adopted to estimate the abundance of tumor-infiltrating immune cells (TICs) and their relationship with the target gene. In the validation section, tissue microarrays (TMAs) of EC and multiplex immunohistochemistry (m-IHC) were evaluated to validate the expression of TNFRSF4, and its correlation with immune markers, including CD4, CD8, and FOXP3. Besides, the receiver operating characteristic (ROC) curve was plotted to determine the diagnostic performance of TNFRSF4, CD4, CD8, and FOXP3 in EC. RESULTS: Two genes, TNFRSF4 and S1PR4, were screened out from 386 intersection differential expression genes (DEGs) shared by ImmuneScore and StromalScore in EC. Highlighted by TNFRSF4, we found that it was not only positively correlated with the TICs (mainly CD4+ T cells, CD8+ T cells, and Tregs) but significantly related to the prognosis in patients of EC, both verified by data from The Cancer Genome Altas (TCGA)-EC database and clinical samples. At the same time, the expression trend of TNFRSF4 was further confirmed by an integrated meta-analysis based on six microarrays from the Gene Expression Omnibus database (GEO). CONCLUSIONS: Collectively, TNFRSF4, a previously unrecognized key player in EC, could serve as a potential biomarker for prognosis prediction and immunomodulation of EC.

Hydrogen Sulfide Diminishes Activation of Adventitial Fibroblasts Through the Inhibition of Mitochondrial Fission.

ABSTRACT: Activation of adventitial fibroblasts (AFs) on vascular injury contributes to vascular remodeling. Hydrogen sulfide (H2S), a gaseous signal molecule, modulates various cardiovascular functions. The aim of this study was to explore whether exogenous H2S ameliorates transforming growth factor-ß1 (TGF-ß1)-induced activation of AFs and, if so, to determine the underlying molecular mechanisms. Immunofluorescent staining and western blot were used to determine the expression of collagen I and α-smooth muscle actin. The proliferation and migration of AFs were performed by using cell counting Kit-8 and transwell assay, respectively. The mitochondrial morphology was assessed by using MitoTracker Red staining. The activation of signaling pathway was evaluated by western blot. The mitochondrial reactive oxygen species and mitochondrial membrane potential were determined by MitoSOX and JC-1 (5,5',6,6'-tetrachloro-1,1,3,3'-tetraethylbenzimidazolyl carbocyanine iodide) staining. Our study demonstrated exogenous H2S treatment dramatically suppressed TGF-ß1-induced AF proliferation, migration, and phenotypic transition by blockage of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and regulated mitochondrial reactive oxygen species generation. Moreover, exogenous H2S reversed TGF-ß1-induced mitochondrial fission and AF activation by modulating Rho-associated protein kinase 1-dependent phosphorylation of Drp1. In conclusion, our results suggested that exogenous H2S attenuates TGF-ß1-induced AF activation through suppression of Drp1-mediated mitochondrial fission in a Rho-associated protein kinase 1-dependent fashion.

Concurrent mutations of germline GPR101 and somatic USP8 in a pediatric giant pituitary ACTH adenoma: a case report.

BACKGROUND: Cushing's disease (CD) is rare in pediatric patients. It is characterized by elevated plasma adrenocorticotropic hormone (ACTH) from pituitary adenomas, with damage to multiple systems and development. In recent years, genetic studies have shed light on the etiology and several mutations have been identified in patients with CD. CASE PRESENTATION: A girl presented at the age of 10 years and 9 months with facial plethora, hirsutism and acne. Her vision and eye movements were impaired. A quick weight gain and slow growth were also observed. Physical examination revealed central obesity, moon face, buffalo hump, supra-clavicular fat pads and bruising. Her plasma ACTH level ranged between 118 and 151 pg/ml, and sella enhanced MRI showed a giant pituitary tumor of 51.8 × 29.3 × 14.0 mm. Transsphenoidal pituitary debulk adenomectomy was performed and immunohistochemical staining confirmed an ACTH-secreting adenoma. Genetic analysis identified a novel germline GPR101 (p.G169R) and a somatic USP8 (p. S719del) mutation. They were hypothesized to impact tumor growth and function, respectively. CONCLUSIONS: We reported a rare case of pediatric giant pituitary ACTH adenoma and pointed out that unusual concurrent mutations might contribute to its early onset and large volume.

Comparison of short-term outcomes between totally laparoscopic right colectomy and laparoscopic-assisted right colectomy: a retrospective study in a single institution on 300 consecutive patients.

BACKGROUND: Laparoscopic surgery has become the standard surgical approach for the treatment of colon cancer. However, the surgical procedure for right colectomy is not standardized. Selection between laparoscopy-assisted right colectomy (LARC) with extracorporeal anastomosis and totally laparoscopic procedures with intracorporeal anastomosis is still a hot topic. The aim of this study was to compare the short-term outcomes of totally laparoscopic right colectomy (TLRC) and LARC in the treatment of right colon cancer. METHODS: This was a retrospective and single-center study conducted between January 2016 and December 2019 featuring 120 TLRC patients and 180 LARC patients following the principles of the CME. We then collated and analyzed the clinicopathological characteristics, operative characteristics, and short-term outcomes. RESULTS: The baseline characteristics were balanced between two groups. TLRC was associated with a significantly lower estimated blood loss (p < 0.01), a shorter incision length (p < 0.01). In terms of postoperative recovery, patients in TLRC group were better, as confirmed by less postoperative pain (p < 0.01), less rescue analgesic usage (p = 0.04), faster to flatus (p < 0.01), defecation (p < 0.01), oral intake (p < 0.01) and discharge (p < 0.01). Incidence of postoperative complications according to Clavien-Dindo classification system was also similar in both groups. CONCLUSIONS: Our data demonstrate that TLRC is technically safe and feasible. This technique could lead to a better cosmetic outcome, a less pain experience and a faster recovery of bowel function.

Enhanced Visible-Light-Driven Photocatalytic Activity by Fe(Ш)-Doped Graphitic C3N4.

Fe(Ш)-doped graphitic carbon nitride (Fe(Ш)-CN) photocatalysts with various Fe(Ш) ions content were prepared via ultrasonic method. Detailed physical characterization indicated that Fe(Ш) ions had been successfully doped into the frame of g-C3N4. The photocatalytic activities were investigated, and methyl orange (MO) and tetracycline hydrochloride (TC) were used as the targeted pollutants. The as-prepared Fe(Ш)-CN materials exhibited higher photocatalytic activities than those of the pure g-C3N4. Specifically, the degradation rate of 2Fe(Ш)-CN under visible light was 2.06 times higher for MO and 2.65 times higher for TC than that of g-C3N4. The increased photocatalytic activities of Fe(Ш)-CN were mainly attributed to the enhanced light absorption ability and the rapid separation of photogenerated carriers. Moreover, the importance of active species during the reaction process was also explored, and the results indicated that •O2- is the main active species.

[Expression and Role of PD-L1 in a Mouse Model of Necrotizing Enterocolitis].

Objective: To investigate the expression and role of programmed death ligand-1 (PD-L1) in a mouse model of necrotizing enterocolitis (NEC). Methods: A total of 20 wild-type C57 BL/6 J mice were randomly assigned to the control and the model groups. Mice in the control group were breastfed, while mice in the model group were given lipopolysaccharide, formula feeding, hypoxia, and cold stimulation for NEC induction. Then, the intestines of the mice were collected in order to assess the pathological changes through HE staining, to examine PD-L1 expression and localization with immunofluorescence co-localization, and to evaluate intestinal PD-L1 expression with Western blot. Peripheral blood was collected for flow cytometry to examine leukocyte subpopulations and their PD-L1 expression. On the other hand, 14 PD-L1 (+/+) mice and 14 PD-L1 (-/-) mice were randomly divided into their respective genotype control groups and model groups. The same induction method as was already mentioned was adopted for the model groups. The intestines of the mice were collected for HE staining to evaluate the pathological change and peripheral blood was collected to examine the expression of inflammatory factors. Results: The NEC mouse model was successfully constructed. PD-L1 was widely expressed in enterocytes and inflammatory cells in the mouse intestines and in T cells, monocytes, and neutrophils in peripheral blood. The expression of PD-L1 in NEC mouse intestines increased in comparison with that of the control group. In the peripheral blood of NEC mice, the proportion of T cells and monocytes and their PD-L1 expression showed no significant changes compared with those of the control group, while the proportion of neutrophils and their PD-L1 expression increased by about 140% and 150%, respectively, in comparison with those of the control group ( P<0.05). According to the results of the PD-L1 gene mouse experiment, the control groups of PD-L1 (+/+) mice and PD-L1 (-/-) mice showed no significant difference in their intestinal conditions and serum inflammatory factor levels, while the PD-L1 (-/-) NEC mouse had worse intestinal pathological changes and increased mean pathological scores compared with those of PD-L1 (+/+) NEC mouse ( P<0.05). In addition, serum interleukin (IL)-10 in PD-L1 (-/-) NEC mouse decreased by about 44% compared with that of PD-L1 (+/+) NEC mice, and chemokine (C-X-C motif) ligand 1/IL-6/IL-1ß all increased by more than 25% (all P<0.05). Conclusion: PD-L1 is widely expressed in inflammatory cells and enterocytes in mice. Knocking out PD-L1 aggravates the degree of NEC inflammation and intestinal pathological changes. PD-L1 plays a protective role by reducing inflammation in the pathogenesis of NEC, the mechanism of which may be related to the regulation of neutrophils/enterocytes.

The Mutational Features of Aristolochic Acid-Induced Mouse and Human Liver Cancers.

BACKGROUND AND AIMS: Aristolochic acid (AA) exposure has been statistically associated with human liver cancers. However, direct evidence of AA exposure-induced liver cancer is absent. This study aims to establish a direct causal relationship between AA exposure and liver cancers based on a mouse model and then explores the AA-mediated genomic alterations that could be implicated in human cancers with AA-associated mutational signature. APPROACH AND RESULTS: We subjected mice, including phosphatase and tensin homolog (Pten)-deficient ones, to aristolochic acid I (AAI) alone or a combination of AAI and CCl4 . Significantly, AAI exposure induced mouse liver cancers, including hepatocellular carcinoma (HCC) and combined HCC and intrahepatic cholangiocarcinoma, in a dose-dependent manner. Moreover, AAI exposure also enhanced tumorigenesis in these CCl4 -treated or Pten-deficient mice. AAI led to DNA damage and AAI-DNA adduct that could initiate liver cancers through characteristic adenine-to-thymine transversions, as indicated by comprehensive genomic analysis, which revealed recurrent mutations in Harvey rat sarcoma virus oncogene. Interestingly, an AA-associated mutational signature was mainly implicated in human liver cancers, especially from China. Moreover, we detected the AAI-DNA adduct in 25.8% (16/62) of paratumor liver tissues from randomly selected Chinese patients with HCC. Furthermore, based on phylogenetic analysis, the characteristic mutations were found in the initiating malignant clones in the AA-implicated mouse and human liver cancers where the mutations of tumor protein p53 and Janus kinase 1 were prone to be significantly enriched in the AA-affected human tumors. CONCLUSIONS: This study provides evidence for AA-induced liver cancer with the featured mutational processes during malignant clonal evolution, laying a solid foundation for the prevention and diagnosis of AA-associated human cancers, especially liver cancers.

Does Additional Laparoscopic-Assisted Surgery after Endoscopic Submucosal Dissection Affect Short Outcomes in Patients with Stage T1 Colorectal Cancer? A Propensity Score-Based Analysis.

BACKGROUND: Additional surgery is necessary in cases with non-curative endoscopic submucosal dissection. It is still unknown whether preceding endoscopic submucosal dissection (ESD) for T1 colorectal carcinoma affects the short outcomes of patients who underwent additional surgery or not as compared with surgery alone without ESD. METHODS: Patients (101 pairs) with T1 colorectal cancer who underwent additional laparoscopic-assisted surgery after endoscopic submucosal dissection (additional surgery group, n = 101) or laparoscopic-assisted surgery alone (surgery alone group, n = 101) were matched (1:1). Short-term morbidity, operation outcomes, and lymph node metastasis of the resected specimen were compared. RESULTS: There were no significant differences between the additional laparoscopic-assisted surgery and laparoscopic-assisted surgery alone groups in lymph node metastasis (9.9 vs. 5.9%, respectively, p = 0.297), operative time (147.76 ± 52.00 min vs. 156.50 ± 54.28 min, p = 0.205), first flatus time (3.56 ± 1.10 days vs. 3.63 ± 1.05 days, p = 0.282), first stool time (4.30 ± 1.04 days vs. 4.39 ± 1.22 days, p = 0.293), time to intake (5.00 ± 1.18 days vs. 5.25 ± 1.39 days, p = 0.079), blood loss (44.75 ± 45.40 mL vs. 60.40 ± 78.98 mL, p = 0.603), harvest lymph nodes (18.74 ± 7.22 vs. 20.32 ± 9.69, p = 0.438), postoperative surgical complications (p = 0.733), and postoperative length of hospital stay (8.68 ± 4.00 days vs. 8.39 ± 1.94 days, p = 0.401). CONCLUSION: ESD did not increase the difficulty of additional laparoscopic-assisted surgery, hospital stay, or the incidence of postoperative complications. Additional laparoscopic-assisted surgery is safe and recommended for patients with T1 cancer at high risk of lymph node metastasis and residual cancer after non-curative ESD.

T2 mapping of the acetabular cartilage in infants and children with developmental dysplasia of the hip.

BACKGROUND: T2 mapping is useful for evaluating the cartilage matrix. PURPOSE: To determine the variations in the acetabular cartilage T2 relaxation values between healthy individuals and those with developmental dysplasia of the hip (DDH). MATERIAL AND METHODS: Thirty-three patients with unilateral DDH underwent 3-T magnetic resonance imaging (MRI) between January 2018 and February 2019. Fifteen volunteers (30 hips) were enrolled as controls. T2 values were measured with the T2 mapping sequence in all layers and were equally divided into three layers (deep, middle, and superficial) with equal thickness. We calculated the mean T2 relaxation values for the full thickness, deep, middle, and superficial layers and compared the values between the different groups. In addition, the inter- and intra-observer agreements were calculated. RESULTS: The T2 relaxation values in the DDH arm were significantly lower in the middle, superficial, and full thickness layers compared with those of the volunteers and contralateral hips. The T2 relaxation values of the deep layers showed no significant difference between the different groups. The acetabular cartilage T2 relaxation values increased from the deep layer to the superficial layer in the control and contralateral groups. Both inter- and intra-observer agreements were good. CONCLUSION: MRI T2 mapping may help to diagnose developmental disorders of the acetabular cartilage matrix in infants and children with DDH. Abnormal acetabular cartilage T2 relaxation values may be due to the extraordinary stress load of the femoral head.