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The preliminary study revealed that the ethyl acetate eluate of Youngia japonica (YJ-E) could inhibit the expression of key proteins of p-p65, p-IκBα, p-IKKα/β, and p-AKT in LPS stimulated BV2 cell. Further phytochemical study led to the isolation of eight compounds from YJ-E, including one new sesquiterpene lactone. Their structures were elucidated by several spectroscopic data, and comparing the NMR data of known compound. In addition, all of the isolates were evaluated for the anti-inflammatory effect. As a result, compounds 3 and 4 distinctly attenuated the expressions of p-IκBα, p-p65, and p-AKT in LPS stimulated BV2 cell, respectively.

A two-step strategy has been established for the enantioselective synthesis of 4-aminoquinolines possessing axial chirality. This approach involves a chiral phosphoric acid-catalyzed cycloaddition, followed by a DDQ oxidation step. The method offers efficient access to a variety of 1,1'-biaryl-2,2'-amino alcohol derivatives in excellent yields and enantioselectivities (up to 98% yield and 93% ee). Furthermore, the synthetic transformation of the products was also investigated.

Pancreatoblastoma, a rare pancreatic tumor, exhibits diverse differentiation pathways, including acinar, ductal, and neuroendocrine lineages, often with distinct squamoid nests [3]. We present a notable case of pancreatoblastoma coexisting with large cell neuroendocrine carcinoma in a 10-year-old boy, presenting with abdominal discomfort, weight loss, and lesions in the pancreas, spleen, and liver visible on imaging. A liver biopsy revealed a poorly differentiated carcinoma with neuroendocrine features, while a splenic biopsy showed acinar cell differentiation, raising possible diagnoses of pancreatoblastoma or acinar cell carcinoma. Subsequent surgical resection after chemotherapy revealed diverse components within the pancreatoblastoma, including well-differentiated acinar and neuroendocrine cells, squamoid nests, and a high-grade neuroendocrine carcinoma. Genetic analysis detected pathogenic variants in TP53 and SMAD4, rarely found in pancreatoblastomas. This juxtaposition of large cell neuroendocrine carcinoma and pancreatoblastoma suggests a potential evolution from well-differentiated neuroendocrine tumors to poorly-differentiated carcinomas within pancreatoblastomas., Competing Interests: The authors declare no conflict of interest., (Published by Oxford University Press and JSCR Publishing Ltd. © The Author(s) 2024.)

Background: Lumbar disc herniation (LDH) is common in aged human beings. This study is to investigate the prevalence of lumbar disc herniation (LDH) in different symptomatic populations attending outpatient clinics based on magnetic resonance imaging (MRI) studies, and to analyze the characteristics, distribution, and treatment strategies thereof., Methods: Patients who visited our outpatient clinics between January 1, 2022, and December 31, 2022, with complaints of low back pain, either accompanied or unaccompanied by lower limb symptoms (radiating pain, numbness or muscle weakness), were included. All patients underwent comprehensive lumbar spine MRI examinations. The prevalence of LDH in different symptomatic populations, as well as the characteristics, distribution, and treatment strategies of disc herniation were analyzed., Results: Among 8,161 individuals (3,411 males and 4,750 females), 4,496 were diagnosed with LDH, resulting in a prevalence of 55.1 %. Of these, 683 (15.2 %) individuals underwent surgical treatment. Among all patients, 3,529 exhibited only low back pain symptoms, 1,820 (51.6 %) were diagnosed with LDH, and 201 (11.0 %) received surgical treatment. Additionally, 2,673 patients with low back pain accompanied by lower limb symptoms were identified, with 1,608 individuals (82.1 %) diagnosed with LDH; 319 (19.8 %) underwent surgical treatment. Furthermore, 1,959 patients presented with lower limb symptoms only, 1,068 (54.5 %) were diagnosed with LDH, and 163 received surgical treatment (P < 0.001). The prevalence rate for males was 58.8 %, compared to females with 52.4 % (P < 0.01). The prevalence of LDH exhibited an initially increasing trend, later decreasing with advancing age. L4/5 and L5/S1 were the most commonly affected segments., Conclusion: LDH prevalence varies among patients with different symptoms, with a higher rate in those presenting with low back pain accompanied by lower limb symptoms. These symptomatic patients also exhibit a higher rate of surgical intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In the process of searching for anti-breast cancer agents, five sesquiterpene lactones (1-5), including two previously undescribed ones, yjaponica B-C (1-2), were isolated from the herb of Youngia japonica. Their structures were elucidated by spectroscopic data analyses and Marfey's method. Cytotoxic activities of all compounds against A549, U87, and 4T1 cell lines were tested using the CCK8 assay. The result showed that compound 3 possessed the highest cytotoxic activity against 4T1 cells with an IC 50 value of 10.60 μM. Furthermore, compound 3 distinctly induced apoptosis, inhibited immigration, and blocked the cell cycle of 4T1 cells. In addition, compound 3 induced the production of reactive oxygen species. Further anticancer mechanism studies showed that compound 3 significantly upregulated expression of the cleaved caspase 3 and PARP, whereas it downregulated the expression of Bcl-2, cyclin D1, cyclin A2, CDK4, and CDK2. Taken together, our results demonstrate that compound 3 has a high potential of being used as a leading compound for the discovery of new anti-breast cancer agent., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Objectives: Immune checkpoint inhibitors, a revolutionary class of cancer immunotherapy drugs, have transformed cancer treatment by bolstering antitumor immunity for various advanced-stage solid cancers. The US Food and Drug Administration has approved 7 immune checkpoint inhibitors that target 3 major immune checkpoint proteins: cytotoxic T-lymphocyte-associated protein 4, programmed cell death 1 protein, and programmed cell death 1 ligand 1. In addition to their remarkable efficacy, however, these inhibitors have been observed causing immune-related adverse events, particularly immune checkpoint inhibitor-related colitis, which often results in severe or life-threatening clinical issues., Methods: The diagnosis of immune checkpoint inhibitor-related colitis relies on incorporation of clinical evaluation as well as endoscopic and histopathologic examination, with exclusion of other potential etiologies., Results: The common histopathologic manifestations of immune checkpoint inhibitor-related colitis are acute active colitis, chronic active colitis, microscopic colitis (collagenous or lymphocytic), and ischemic colitis, with patterns overlapping. Notably, enterocyte apoptosis is a unique feature of immune checkpoint inhibitor toxicity. The proposed mechanisms for the pathogenesis of immune checkpoint inhibitor-related colitis are primarily associated with autoimmune-type dysregulation and gut microbiome alteration. This review summarizes the clinical and pathologic characteristics of immune checkpoint inhibitor-related colitis and elucidates its underlying pathogenic mechanisms., Conclusions: Future successful management of this form of colitis relies on our comprehension of the intricate interplay between tumoral and systemic immune responses to immune checkpoint inhibitors and innovative approaches to modify these responses, along with specific immune cell populations, to preclude immune-related adverse events while achieving antitumor therapeutic outcomes., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society for Clinical Pathology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Leak following surgical repair of traumatic duodenal injuries results in prolonged hospitalization and oftentimes nil per os(NPO) treatment. Parenteral nutrition(PN) has known morbidity; however, duodenal leak(DL) patients often have complex injuries and hospital courses resulting in barriers to enteral nutrition(EN). We hypothesized EN alone would be associated with 1)shorter duration until leak closure and 2)less infectious complications and shorter hospital length of stay(HLOS) compared to PN., Methods: This was a post-hoc analysis of a retrospective, multicenter study from 35 Level-1 trauma centers, including patients >14 years-old who underwent surgery for duodenal injuries(1/2010-12/2020) and endured post-operative DL. The study compared nutrition strategies: EN vs PN vs EN + PN using Chi-Square and Kruskal-Wallis tests; if significance was found pairwise comparison or Dunn's test were performed., Results: There were 113 patients with DL: 43 EN, 22 PN, and 48 EN + PN. Patients were young(median age 28 years-old) males(83.2%) with penetrating injuries(81.4%). There was no difference in injury severity or critical illness among the groups, however there were more pancreatic injuries among PN groups. EN patients had less days NPO compared to both PN groups(12 days[IQR23] vs 40[54] vs 33[32],p = <0.001). Time until leak closure was less in EN patients when comparing the three groups(7 days[IQR14.5] vs 15[20.5] vs 25.5[55.8],p = 0.008). EN patients had less intra-abdominal abscesses, bacteremia, and days with drains than the PN groups(all p < 0.05). HLOS was shorter among EN patients vs both PN groups(27 days[24] vs 44[62] vs 45[31],p = 0.001). When controlling for predictors of leak, regression analysis demonstrated EN was associated with shorter HLOS(β -24.9, 95%CI -39.0 to -10.7,p < 0.001)., Conclusion: EN was associated with a shorter duration until leak closure, less infectious complications, and shorter length of stay. Contrary to some conventional thought, PN was not associated with decreased time until leak closure. We therefore suggest EN should be the preferred choice of nutrition in patients with duodenal leaks whenever feasible., Level of Evidence: IV., Competing Interests: Conflict of Interest: All JTACS disclosure forms have been supplied and are provided as supplemental digital content (http://links.lww.com/TA/D807)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Fourteen sesquiterpenes, including one undescribed sesquiterpene lactone, were isolated from Youngia japonica, and their structures were identified by NMR, HRESIMS, ECD and calculated ECD. Cytotoxic activities of all isolates against A549, HeLa, and 4 T1 cell lines were detected by CCK8 assay. Among them, 2 showed obvious cytotoxic activity against A549 cells. Subsequently, the production of ROS, and apoptosis of A549 cells treated with 2 were evaluated. The result showed that 2 distinctly increased the ROS level, and induced the apoptosis of A549 cells. Further anticancer mechanism studies showed that 2 increased the expression of cleaved caspase 3. Taken together, our results demonstrated that 2 might become potential leading compounds for the treatment of lung cancer., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Four undescribed coumarin derivatives, ficusalt A (1) and ficusalt B (2), a pair of racemic coumarins, (±) ficudimer A (3a/3b), along with ten known amides, were isolated from the roots of Ficus hirta. Their structures were elucidated by several spectroscopic data analyses, including HRESIMS, NMR, and X-ray single-crystal diffraction. The cytotoxic activities of all compounds against HeLa, HepG2, MCF-7, and H460 cell lines were detected using the MTT assay. Among these, 5 showed the highest activity against HeLa cells. Subsequently, the apoptotic, anti-invasive, and anti-migration effects of 5 on HeLa cells were determined by flow cytometer, transwell invasion assay, and wound-healing assay, respectively. The result suggested that 5 distinctly induced the apoptosis in HeLa cells and inhibited their invasion and migration. Further studies on anticancer mechanisms were conducted using Western blotting. As a result, 5 increased the cleavage of PARP and the expression of pro-apoptotic protein Bax. Moreover, 5 notably upregulated the phosphorylation of p38 and JNK, whereas inhibited the expression of p-ERK and p-AKT. Our results demonstrated that 5 could be a potential leading compound for further application in the treatment of cervical cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Although parasitic copepods of the genus Ergasilus von Nordmann, 1832 are globally distributed parasites of fish, their phylogenetic relationships with other Copepoda are not clear, and the characteristics of their mitochondrial genomes (mitogenomes) are not thoroughly understood. The objective of this study was to address these knowledge gaps by sequencing the complete mitogenome of Ergasilus tumidus Markevich, 1940. The complete mitogenome (GenBank Acc. No. OQ596537) was 14,431 bp long and it comprised 13 protein-coding genes (PCGs), 22 tRNAs, two tRNAs, and two control regions (CRs). Phylogenetic analyses, conducted using concatenated nucleotide and amino acid sequences of 13 protein-coding genes, produced two partially incongruent topologies. While the order Calanoida was consistently resolved as the sister lineage to the other three orders, topological instability was observed in the relationships of the orders Cyclopoida, Siphonostomatoida and Harpacticoida. Siphonostomatoida clustered with Cyclopoida in the nucleotide-based phylogeny, but with Harpacticoida in the amino acid-based phylogeny. The latter topology conforms to the widely accepted relationships, but we speculate that the former topology is more likely to be the correct one. Our study provides a complete mitogenome sequence of E. tumidus, which helps us better understand the molecular evolution of the genus Ergasilus. Additionally, we suggest a different perspective on the controversial phylogenetic relationships among Siphonostomatoida, Cyclopoida and Harpacticoida, diverging from previously accepted views.

This study aimed to investigate the effects of the oat hay feeding method and compound probiotics (CMP) on the growth, health, serum antioxidant and immune indicators, rumen fermentation, and bacteria community of dairy calves from 3 to 5 months of age. Forty-eight female Holstein calves (80 ± 7 days of age, 93.71 ± 5.33 kg BW) were selected and randomly divided into four groups. A 2 × 2 factorial design was adopted for the experiment, with the factors of the oat hay feeding method (fed as free-choice or 16.7% in the diet) and compound probiotics (CMP) inclusion (0.15% or 0%) in the pelleted starter. The results showed that, compared with giving oat hay as free-choice, feeding a diet of 16.7% oat hay increased the pelleted starter intake at 1-84 d ( p < 0.05), with an average daily gain (ADG) at 61-84 d ( p = 0.02); adding CMP to the pelleted starter did not significantly affect body weight, and reduced the fecal index ( p < 0.05). Feeding 16.7% oat hay increased the concentration of IgA, IgG, and IgM ( p < 0.01), while adding CMP increased the catalase ( p < 0.01) and decreased the concentration of malondialdehyde ( p < 0.01) in serum. Feeding 16.7% oat hay increased the ruminal concentration of propionic acid ( p < 0.05) and isobutyric acid ( p = 0.08), and decreased the ruminal pH ( p = 0.08), the concentration of acetic acid ( p < 0.05), and the ratio of acetic acid to propionic acid ( p < 0.01). Feeding 16.7% oat hay reduced the relative abundance of ruminal Firmicutes , Unidentified-Bacteria, Actinobacteria , Prevotella , NK4A214-group , Olsenella , and Actinobacteriota ( p < 0.05); adding CMP increased the relative abundance of ruminal Prevotella , Rikenellaceae-RC9-gut-group , Ruminococcus , NK4A214-group , and Ruminococcus ( p < 0.05), and decreased the abundance of Desulfobacterora , Prevotella-7 , and Erysipelotricaceae-UCG-002 ( p < 0.05). In conclusion, feeding a diet of 16.7% oat hay increased the pelleted starter intake and average daily gain, while slightly reducing the ruminal pH values; adding CMP to the pelleted starter resulted in reduced diarrhea incidence, increased serum antioxidant capacity and immunity, as well as ruminal richness and diversity of microorganisms in dairy calves from 3 to 5 months of age.

Background: Duodenal leak is a feared complication of repair, and innovative complex repairs with adjunctive measures (CRAM) were developed to decrease both leak occurrence and severity when leaks occur. Data on the association of CRAM and duodenal leak are sparse, and its impact on duodenal leak outcomes is nonexistent. We hypothesized that primary repair alone (PRA) would be associated with decreased duodenal leak rates; however, CRAM would be associated with improved recovery and outcomes when leaks do occur., Methods: A retrospective, multicenter analysis from 35 Level 1 trauma centers included patients older than 14 years with operative, traumatic duodenal injuries (January 2010 to December 2020). The study sample compared duodenal operative repair strategy: PRA versus CRAM (any repair plus pyloric exclusion, gastrojejunostomy, triple tube drainage, duodenectomy)., Results: The sample (N = 861) was primarily young (33 years) men (84%) with penetrating injuries (77%); 523 underwent PRA and 338 underwent CRAM. Complex repairs with adjunctive measures were more critically injured than PRA and had higher leak rates (CRAM 21% vs. PRA 8%, p < 0.001). Adverse outcomes were more common after CRAM with more interventional radiology drains, prolonged nothing by mouth and length of stay, greater mortality, and more readmissions than PRA (all p < 0.05). Importantly, CRAM had no positive impact on leak recovery; there was no difference in number of operations, drain duration, nothing by mouth duration, need for interventional radiology drainage, hospital length of stay, or mortality between PRA leak versus CRAM leak patients (all p > 0.05). Furthermore, CRAM leaks had longer antibiotic duration, more gastrointestinal complications, and longer duration until leak resolution (all p < 0.05). Primary repair alone was associated with 60% lower odds of leak, whereas injury grades II to IV, damage control, and body mass index had higher odds of leak (all p < 0.05). There were no leaks among patients with grades IV and V injuries repaired by PRA., Conclusion: Complex repairs with adjunctive measures did not prevent duodenal leaks and, moreover, did not reduce adverse sequelae when leaks did occur. Our results suggest that CRAM is not a protective operative duodenal repair strategy, and PRA should be pursued for all injury grades when feasible., Level of Evidence: Therapeutic/Care Management; Level IV., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Study Design: A retrospective study., Objective: Traumatic cervical spinal cord injury (TSCI) is often associated with disc rupture. It was reported that high signal of disc and anterior longitudinal ligament (ALL) rupture on magnetic resonance imaging (MRI) were the typical signs of ruptured disc. However, for TSCI with no fracture or dislocation, there is still difficult to diagnose disc rupture. The purpose of this study was to investigate the diagnostic efficiency and localization method of different MRI features for cervical disc rupture in patient with TSCI but no any signs of fracture or dislocation., Setting: Affiliated hospital of University in Nanchang, China., Methods: Patients who had TSCI and underwent anterior cervical surgery between June 2016 and December 2021 in our hospital were included. All patients received X-ray, CT scan, and MRI examinations before surgery. MRI findings such as prevertebral hematoma, high-signal SCI, high-signal posterior ligamentous complex (PLC), were recorded. The correlation between preoperative MRI features and intraoperative findings was analyzed. Also, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of these MRI features in diagnosing the disc rupture were calculated., Results: A total of 140 consecutive patients, 120 males and 20 females with an average age of 53 years were included in this study. Of these patients, 98 (134 cervical discs) were intraoperatively confirmed with cervical disc rupture, but 59.1% (58 patients) of them had no definite evidence of an injured disc on preoperative MRI (high-signal disc or ALL rupture signal). For these patients, the high-signal PLC on preoperative MRI had the highest diagnostic rate for disc rupture based on intraoperative findings, with a sensitivity of 97%, specificity of 72%, PPV of 84% and NPV of 93%. Combined high-signal SCI with high-signal PLC had higher specificity (97%) and PPV (98%), and a lower FPR (3%) and FNR (9%) for the diagnosis of disc rupture. And combination of three MRI features (prevertebral hematoma, high-signal SCI and PLC) had the highest accuracy in diagnosing traumatic disc rupture. For the localization of the ruptured disc, the level of the high-signal SCI had the highest consistency with the segment of the ruptured disc., Conclusion: MRI features, such as prevertebral hematoma, high-signal SCI and PLC, demonstrated high sensitivities for diagnosing cervical disc rupture. High-signal SCI on preoperative MRI could be used to locate the segment of ruptured disc., (© 2023. The Author(s), under exclusive licence to International Spinal Cord Society.)

Background: Unplanned reoperation is commonly performed due to postoperative complications. Previous studies have reported the incidence of unplanned reoperation following lumbar spinal surgery. But few study focused on the trend of reoperation rates, and the reasons of unplanned reoperation were not clear. In this study, we conducted a retrospective study to determine the trend of unplanned reoperation rates after degenerative lumbar spinal surgery from 2011 to 2019, and the reasons and risk factors of unplanned reoperation were also determined., Methods: Data of patients who were diagnosed with degenerative lumbar spinal disease and underwent posterior lumbar spinal fusion surgery in our institution from January 2011 to December 2019 were reviewed. Those who received unplanned reoperation during the primary admission were identified. The demographics, diagnosis, surgical segments and postoperative complications of these patients were recorded. The rates of unplanned reoperation from 2011 to 2019 were calculated, and the reasons of unplanned reoperation were statistically analysed., Results: A total of 5289 patients were reviewed. Of them, 1.91% (n = 101) received unplanned reoperation during the primary admission. The unplanned reoperation rates of degenerative lumbar spinal surgery firstly increased from 2011 to 2014, with a peak rate in 2014 (2.53%). Then, the rates decreased from 2014 to 2019, with the lowest one in 2019 (1.46%). Patients with lumbar spinal stenosis have a higher rate of unplanned reoperation (2.67%) compared with those diagnosed as lumbar disc herniation (1.50%) and lumbar spondylolisthesis (2.04%) (P < 0.05). The main reasons for unplanned reoperation were wound infection (42.57%), followed by wound hematoma (23.76%). Patients who underwent 2-segment spinal surgery had a higher unplanned reoperation rate (3.79%) than those receiving other segments surgery (P < 0.001). And different spine surgeons had different reoperation rates., Conclusions: The rates of unplanned reoperation after lumbar degenerative surgery increased at first and then decreased during past 9 years. Wound infection was the major reason for unplanned reoperation. 2-segment surgery and surgeon's surgical skills were related to the reoperation rate., (© 2023 Royal Australasian College of Surgeons.)

To meet the increasing need for low-cost, compact imaging technology with cellular resolution, we have developed a microLED-based structured light sheet microscope for three-dimensional ex vivo and in vivo imaging of biological tissue in multiple modalities. All the illumination structure is generated directly at the microLED panel-which serves as the source-so light sheet scanning and modulation is completely digital, yielding a system that is simpler and less prone to error than previously reported methods. Volumetric images with optical sectioning are thus achieved in an inexpensive, compact form factor without any moving parts. We demonstrate the unique properties and general applicability of our technique by ex vivo imaging of porcine and murine tissue from the gastrointestinal tract, kidney, and brain., Competing Interests: R.L. is the founder of Light Research Inc., which didn’t support this research., (© 2023 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Purpose: To study the accuracy of non-invasive chromosomal screening (NICS) results, in normal chromosomes and chromosomal rearrangement groups and to investigate whether using trophoblast cell biopsy along with NICS, to choose embryos for transfer can improve the clinical outcomes of assisted pregnancy. Methods: We retrospectively analyzed 101 couples who underwent preimplantation genetic testing at our center from January 2019 to June 2021 and collected 492 blastocysts for trophocyte (TE) biopsy. D3-5 blastocyst culture fluid and blastocyst cavity fluid were collected for the NICS. Amongst them, 278 blastocysts (58 couples) and 214 blastocysts (43 couples) were included in the normal chromosomes and chromosomal rearrangement groups, respectively. Couples undergoing embryo transfer were divided into group A, in which both the NICS and TE biopsy results were euploid (52 embryos), and group B, in which the TE biopsy results were euploid and the NICS results were aneuploid (33 embryos). Results: In the normal karyotype group, concordance for embryo ploidy was 78.1%, sensitivity was 94.9%, specificity was 51.4%, the positive predictive value (PPV) was 75.7%, and the negative predictive value (NPV) was 86.4%. In the chromosomal rearrangement group, concordance for embryo ploidy was 73.1%, sensitivity was 93.3%, specificity was 53.3%, the PPV was 66.3%, and the NPV was 89%. In euploid TE/euploid NICS group, 52 embryos were transferred; the clinical pregnancy rate was 71.2%, miscarriage rate was 5.4%, and ongoing pregnancy rate was 67.3%. In euploid TE/aneuploid NICS group, 33 embryos were transferred; the clinic pregnancy rate was 54.5%, miscarriage rate was 5.6%, and ongoingpregnancy rate was 51.5%. The clinical pregnancy and ongoing pregnancy rates were higher in the TE and NICS euploid group. Conclusion: NICS was similarly effective in assessing both normal and abnormal populations. Identification of euploidy and aneuploidy alone may lead to the wastage of embryos due to high false positives. More suitable reporting methods for NICS and countermeasures for a high number of false positives in NICS are needed. In summary, our results suggest that combining biopsy and NICS results could improve the outcomes of assisted pregnancy., Competing Interests: Authors Y-xY and JW were employed by the company Yikon Genomics Company Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sun, Wang, Sixi-Wen, Zhou, Zhang, Wu, Qiao, Sun, Yao, Wang, Yi and Qian.)

Purpose: The aim of this study was to established a dynamic nomogram for assessing the risk of bone metastasis in patients with thyroid cancer (TC) and assist physicians to make accurate clinical decisions., Methods: The clinical data of patients with TC admitted to the First Affiliated hospital of Nanchang University from January 2006 to November 2016 were included in this study. Demographic and clinicopathological parameters of all patients at primary diagnosis were analyzed. Univariate and multivariate logistic regression analysis was applied to build a predictive model incorporating parameters. The discrimination, calibration, and clinical usefulness of the nomogram were evaluated using the C-index, ROC curve, calibration plot, and decision curve analysis. Internal validation was evaluated using the bootstrapping method., Results: A total of 565 patients were enrolled in this study, of whom 25 (4.21%) developed bone metastases. Based on logistic regression analysis, age (OR=1.040, P =0.019), hemoglobin (HB) (OR=0.947, P <0.001) and alkaline phosphatase (ALP) (OR=1.006, P =0.002) levels were used to construct the nomogram. The model exhibited good discrimination, with a C-index of 0.825 and good calibration. A C-index value of 0.815 was achieved on interval validation analysis. Decision curve analysis showed that the nomogram was clinically useful when intervention was decided at a bone metastases possibility threshold of 1%., Conclusions: This dynamic nomogram, with relatively good accuracy, incorporating age, HB, and ALP, could be conveniently used to facilitate the prediction of bone metastasis risk in patients with TC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Li, Hong, Zhong, Sun, Huang, Liu and Liu.)

We previously identified a missense single nucleotide polymorphism rs2228315 (G>A, Met62Ile) in the selectin-P-ligand gene ( SELPLG ), encoding P-selectin glycoprotein ligand 1 (PSGL-1), to be associated with increased susceptibility to acute respiratory distress syndrome (ARDS). These earlier studies demonstrated that SELPLG lung tissue expression was increased in mice exposed to lipopolysaccharide (LPS)- and ventilator-induced lung injury (VILI) suggesting that inflammatory and epigenetic factors regulate SELPLG promoter activity and transcription. In this report, we used a novel recombinant tandem PSGL1 immunoglobulin fusion molecule (TSGL-Ig), a competitive inhibitor of PSGL1/P-selectin interactions, to demonstrate significant TSGL-Ig-mediated decreases in SELPLG lung tissue expression as well as highly significant protection from LPS- and VILI-induced lung injury. In vitro studies examined the effects of key ARDS stimuli (LPS, 18% cyclic stretch to simulate VILI) on SELPLG promoter activity and showed LPS-mediated increases in SELPLG promoter activity and identified putative promoter regions associated with increased SELPLG expression. SELPLG promoter activity was strongly regulated by the key hypoxia-inducible transcription factors, HIF-1α, and HIF-2α as well as NRF2. Finally, the transcriptional regulation of SELPLG promoter by ARDS stimuli and the effect of DNA methylation on SELPLG expression in endothelial cell was confirmed. These findings indicate SELPLG transcriptional regulation by clinically-relevant inflammatory factors with the significant TSGL-Ig-mediated attenuation of LPS and VILI highly consistent with PSGL1/P-selectin as therapeutic targets in ARDS., Competing Interests: The authors declare no conflicts of interest., (© 2023 The Authors. Pulmonary Circulation published by John Wiley & Sons Ltd on behalf of Pulmonary Vascular Research Institute.)

Although the progression of non-alcoholic fatty liver disease (NAFLD) from steatosis to steatohepatitis (NASH) and cirrhosis remains poorly understood, a critical role for dysregulated innate immunity has emerged. We examined the utility of ALT-100, a monoclonal antibody (mAb), in reducing NAFLD severity and progression to NASH/hepatic fibrosis. ALT-100 neutralizes eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a novel damage-associated molecular pattern protein (DAMP) and Toll-like receptor 4 (TLR4) ligand. Histologic and biochemical markers were measured in liver tissues and plasma from human NAFLD subjects and NAFLD mice (streptozotocin/high-fat diet-STZ/HFD, 12 weeks). Human NAFLD subjects (n = 5) exhibited significantly increased NAMPT hepatic expression and significantly elevated plasma levels of eNAMPT, IL-6, Ang-2, and IL-1RA compared to healthy controls, with IL-6 and Ang-2 levels significantly increased in NASH non-survivors. Untreated STZ/HFD-exposed mice displayed significant increases in NAFLD activity scores, liver triglycerides, NAMPT hepatic expression, plasma cytokine levels (eNAMPT, IL-6, and TNFα), and histologic evidence of hepatocyte ballooning and hepatic fibrosis. Mice receiving the eNAMPT-neutralizing ALT-100 mAb (0.4 mg/kg/week, IP, weeks 9 to 12) exhibited marked attenuation of each index of NASH progression/severity. Thus, activation of the eNAMPT/TLR4 inflammatory pathway contributes to NAFLD severity and NASH/hepatic fibrosis. ALT-100 is potentially an effective therapeutic approach to address this unmet NAFLD need., (© 2023 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Purpose: Thoracolumbar fracture is one of the most common fractures of spine. And short-segment posterior fixation including the fractured vertebra (SSPFI) is usually used for the surgical treatment of it. However, the outcomes of SSPFI for different types of thoracolumbar fractures are not clear, and whether it is necessary to perform transpedicular bone grafting is still controversial. This study was conducted to determine the clinical efficacy of SSPFI for the treatment of different types of single-level thoracolumbar fracture, and make clear what kind of fractures need transpedicular bone grafting during the surgery., Methods: Patients with single-level thoracolumbar fracture undergoing SSPFI surgery between January 2013 and June 2020 were included in this study. The operative duration, intraoperative blood loss, anterior vertebral height ratio (AVHR) and anterior vertebral height compressive ratio (AVHC) of the fractured vertebra, local kyphotic Cobb angle (LKA), vertebral wedge angle (VWA) and correction loss during follow up period were recorded. Outcomes between unilateral and bilateral pedicle screw fixation for fractured vertebra, between SSPFI with and without transpedicular bone grafting (TBG), and among different compressive degrees of fractured vertebrae were compared, respectively., Results: A total of 161 patients were included in this study. All the patients were followed up, and the mean follow-upped duration was 25.2 ± 3.1 months (6-52 months). At the final follow-up, the AVHR was greater, and the LKA and VWA were smaller in patients with bilateral fixation (6-screw fixation) than those with unilateral fixation (5-screw fixation) of AO type A3/A4 fractures ( P  < 0.001). The correction loss of AVHR, LKA and VWA in fractured vertebra were significantly great when preoperative AVHC was >50% ( P  < 0.05). For patients with AVHC >50%, the correction loss in patients with TBG were less than those without TBG at the final follow-up ( P  < 0.05)., Conclusions: SSPFI using bilateral fixation was more effective than unilateral fixation in maintaining the fractured vertebral height for AO type A3/A4 fractures. For patients with AVHC >50%, the loss of correction was more obvious and it can be decreased by transpedicular bone grafting., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Luo, Liao, Sun, Wu, Zhang, Zhang, Huang, Liu, Zhang and Liu.)

Objective: The purpose of this paper was to develop a machine learning algorithm with good performance in predicting bone metastasis (BM) in non-small cell lung cancer (NSCLC) and establish a simple web predictor based on the algorithm., Methods: Patients who diagnosed with NSCLC between 2010 and 2018 in the Surveillance, Epidemiology and End Results (SEER) database were involved. To increase the extensibility of the research, data of patients who first diagnosed with NSCLC at the First Affiliated Hospital of Nanchang University between January 2007 and December 2016 were also included in this study. Independent risk factors for BM in NSCLC were screened by univariate and multivariate logistic regression. At this basis, we chose six commonly machine learning algorithms to build predictive models, including Logistic Regression (LR), Decision tree (DT), Random Forest (RF), Gradient Boosting Machine (GBM), Naive Bayes classifiers (NBC) and eXtreme gradient boosting (XGB). Then, the best model was identified to build the web-predictor for predicting BM of NSCLC patients. Finally, area under receiver operating characteristic curve (AUC), accuracy, sensitivity and specificity were used to evaluate the performance of these models., Results: A total of 50581 NSCLC patients were included in this study, and 5087(10.06%) of them developed BM. The sex, grade, laterality, histology, T stage, N stage, and chemotherapy were independent risk factors for NSCLC. Of these six models, the machine learning model built by the XGB algorithm performed best in both internal and external data setting validation, with AUC scores of 0.808 and 0.841, respectively. Then, the XGB algorithm was used to build a web predictor of BM from NSCLC., Conclusion: This study developed a web predictor based XGB algorithm for predicting the risk of BM in NSCLC patients, which may assist doctors for clinical decision making., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Li, Liu, Sun, Zhong, Liu, Huang, Zhang and Liu.)

Background: Cerebral small vessel disease (CSVD), which comprises the typical features of white matter hyperintensity (WMH) and Vichor-Robin spaces (VRSs) in the brain, is one of the leading causes of aging-related cognitive decline and, ultimately, contributes to the occurrence of dementia, including Alzheimer's disease (AD)., Objective: To investigate whether CSVD imaging markers modify the pathological processes of AD and whether these markers improve AD diagnosis., Methods: 208 participants were enrolled in the China Aging and Neurodegenerative Initiative (CANDI). Fluid AD biomarkers were detected using a single-molecule array, and cerebral small vessel dysfunction was determined using magnetic resonance imaging., Results: WMH contributed to AD pathology only within the NC and MCI groups (CDR ≤0.5), whereas VRSs had no effect on AD pathology. The associations between AD biomarkers and cognitive mental status were consistent with the presence of CSVD pathology. That is, within individuals without CSVD pathology, the MMSE scores were correlated with AD fluid biomarkers, except for plasma Aβ42 and Aβ40. Increased plasma p-Tau levels were associated with worse cognitive performance in individuals with WMH (β= -0.465, p = 0.0016) or VRSs (β= -0.352, p = 0.0257) pathology. Plasma AD biomarkers combined with CSVD markers showed high accuracy in diagnosing dementia., Conclusion: Findings from this cross-sectional cohort study support the notion that CSVD is a risk factor for dementia and highlights that vascular pathology can promote AD biomarker levels, especially in the early course of the disease. Moreover, our results suggest that adding a vascular category to the ATN framework improves the diagnostic accuracy of AD.

Background: Since 2011, three large-scale genome-wide association studies (GWAS) have confirmed that the CD2AP rs9349407 polymorphism is significantly connected with Alzheimer's disease (AD) in individuals of European descent. Subsequently, this association has been replicated in European populations, but is unclear whether it can be replicated in Chinese. Recently, the correlation between rs9349407 and AD in the Chinese population has become a research hotspot., Objective: To explore the association between rs9349407 polymorphism and AD in the Chinese population., Materials and Methods: Firstly, based on the exclusion and inclusion criteria, we selected 11 independent studies from 8 articles exploring the correlation between rs9349407 variation and AD in Chinese. Secondly, we conducted a meta-analysis based on fixed and random effect models and conducted a heterogeneity test. Thirdly, we used the additive model, dominant model, and recessive model for subgroup analysis., Results: We demonstrated that the CD2AP rs9349407 polymorphism increases AD susceptibility in Chinese populations (OR = 1.33, 95% CI = 1.08-1.64, P = 7.45E-03), which is consistent with the effect observed in Caucasian populations. Additionally, subgroup analysis showed that rs9349407 under the additive model (GG + CC vs. GC, OR = 0.76, 95% CI = 0.61-0.97, P = 2.04E-02) and dominant model (GG + GC vs. CC, OR = 0.49, 95% CI = 0.32-0.74, P = 8.51E-04) were also significantly correlated with AD susceptibility, but not under the recessive model (GG vs. GC + CC, OR = 0.77, 95% CI = 0.58-1.03, P = 7.44E-02)., Conclusion: These existing data suggest that rs9349307 is significantly correlated with the susceptibility to AD in the Chinese population, but future studies with large samples are needed to confirm our findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gao, Hao, Zhao, Li, Wang, Han, Sun, Sun and Liu.)

Background: Osteosarcoma (OS) is one of the malignant bone tumors with strong aggressiveness and poor prognosis. Leucine-rich repeats and immunoglobulin-like domains2 (LRIG2) is closely associated with the poor prognosis of a variety of tumors, but the role of LRIG2 in osteosarcoma and the underlying molecular mechanism remains unclear., Objective: The aim of this study was to determine the function of LRIG2 in OS and the related molecular mechanism on cell proliferation, apoptosis and migration of OS., Methods: The mRNA and protein expression of LRIG2 in OS tissues and cells was detected by qRT-PCR, western blot (WB) assay and immunohistochemistry (IHC). The cell counting Kit-8 (CCK-8), clone formation, transwell, TdT-mediated dUTP Nick-End Labeling (TUNEL) and WB assay were applied to determine the proliferation, migration and apoptosis abilities of OS cells and its molecular mechanisms. Spontaneous metastasis xenografts were established to confirm the role of LRIG2 in vivo., Results: LRIG2 exhibited high expression in OS tissues and OS cell lines and the expression of which was significantly correlated with Enneking stage of patients, knockdown LRIG2 expression significantly inhibited OS cell proliferation, migration and enhanced apoptosis. Silencing LRIG2 also suppressed the growth of subcutaneous transplanted tumor in nude mice. Further, the mechanism investigation revealed that the protein level of cell proapoptotic proteins (Bax, caspase9 and caspase3) all increased attributed to LRIG2 deficiency, whereas expression of anti-apoptotic protein BCL2 decreased. LRIG2 silencing led to the decrease phosphorylation of AKT signaling, a decrease expression of vimentin and N-cadherin. Additionally, silencing LRIG2 significantly decreased the rate of tumor growth and tumor size., Conclusions: LRIG2 acts as an oncogene in osteosarcoma, and it might become a novel target in the treatment of human OS., (© 2022. The Author(s).)

Mendelian-randomization (MR) studies using large-scale genome-wide association studies (GWAS) have identified causal association between educational attainment and Alzheimer's disease (AD). However, the underlying mechanisms are still required to be explored. Here, we conduct univariable and multivariable MR analyses using large-scale educational attainment, cognitive performance, intelligence and AD GWAS datasets. In stage 1, we found significant causal effects of educational attainment on cognitive performance (beta = 0.907, 95% confidence interval (CI): 0.884-0.930, P < 1.145E-299), and vice versa (beta = 0.571, 95% CI: 0.557-0.585, P < 1.145E-299). In stage 2, we found that both increase in educational attainment (odds ratio (OR) = 0.72, 95% CI: 0.66-0.78, P = 1.39E-14) and cognitive performance (OR = 0.69, 95% CI: 0.64-0.75, P = 1.78E-20) could reduce the risk of AD. In stage 3, we found that educational attainment may protect against AD dependently of cognitive performance (OR = 1.07, 95% CI: 0.90-1.28, P = 4.48E-01), and cognitive performance may protect against AD independently of educational attainment (OR = 0.69, 95% CI: 0.53-0.89, P = 5.00E-03). In stage 4, we found significant causal effects of cognitive performance on intelligence (beta = 0.907, 95% CI: 0.877-0.938, P < 1.145E-299), and vice versa (beta = 0.957, 95% CI: 0.937-0.978, P < 1.145E-299). In stage 5, we identified that cognitive performance may protect against AD independently of intelligence (OR = 0.74, 95% CI: 0.61-0.90, P = 2.00E-03), and intelligence may protect against AD dependently of cognitive performance (OR = 1.17, 95% CI: 0.40-3.43, P = 4.48E-01). Collectively, our univariable and multivariable MR analyses highlight the protective role of cognitive performance in AD independently of educational attainment and intelligence. In addition to the intelligence, we extend the mechanisms underlying the associations of educational attainment with AD., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: In colorectal cancer, tumor deposits (TDs) are considered to be a prognostic factor in the current staging system, and are only considered in the absence of lymph node metastases (LNMs). However, this definition and the subsequent prognostic value based on it is controversial, with various hypotheses. TDs may play an independent role when it comes to survival and addition of TDs to LNM count may predict the prognosis of patients more accurately., Aim: To assess the prognostic impact of TDs and evaluate the effect of their addition to the LNM count., Methods: The patients are derived from the Surveillance, Epidemiology, and End Results database. A prognostic analysis regarding impact of TDs on overall survival (OS) was performed using Cox regression model, and other covariates associating with OS were adjusted. The effect of addition of TDs to LNM count on N restaging was also evaluated. The subgroup analysis was performed to explore the different profile of risk factors between patients with and without TDs., Results: Overall, 103755 patients were enrolled with 14131 (13.6%) TD-positive and 89624 (86.4%) TD-negative tumors. TD-positive patients had worse prognosis compared with TD-negative patients, with 3-year OS rates of 47.3% (95%CI, 46.5%-48.1%) and 77.5% (95%CI, 77.2%-77.8%, P < 0.0001), respectively. On multivariable analysis, TDs were associated poorer OS (hazard ratio, 1.35; 95%CI, 1.31-1.38; P < 0.0001). Among TD-positive patients, the number of TDs had a linear negative effect on disease-free survival and OS. After reclassifying patients by adding TDs to the LNM count, 885 of 19 965 (4.4%) N1 patients were restaged as pN2, with worse outcomes than patients restaged as pN1 (3-year OS rate: 78.5%, 95%CI, 77.9%-79.1% vs 63.2%, 95%CI, 60.1%-66.5%, respectively; P < 0.0001)., Conclusion: TDs are an independent prognostic factor for OS in colorectal cancer. The addition of TDs to LNM count improved the prognostic accuracy of tumor, node and metastasis staging., Competing Interests: Conflict-of-interest statement: All the Authors have no conflict of interest related to the manuscript., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

In order to discover pesticidal lead compounds with high activity and low toxicity, a series of novel benzamides substituted with pyrazole-linked 1,2,4-oxadiazole were designed via bioisosterism. The chemical structures of the target compounds were confirmed via 1 H NMR, 13 C NMR and HRMS analysis. The preliminary bioassay showed that most compounds exhibited good lethal activities against Mythimna separate , Helicoverpa armigera , Ostrinia nubilalis and Spodoptera frugiperda at 500 mg/L. Particularly in the case of Mythimna separate , compound 14q (70%) exhibited obvious insecticidal activity. In addition, compound 14h demonstrated good fungicidal activity against Pyricularia oryae with an inhibition rate of 77.8%, and compounds 14e , 14k , 14n and 14r also showed certain antifungal activities (55.6-66.7%). The zebrafish toxicity test showed that the LC 50 of compound 14h was 14.01 mg/L, which indicated that it may be used as a potential leading compound for further structural optimization.

Breast cancer (BC) was the most common malignant tumor in women, and breast infiltrating ductal carcinoma (IDC) accounted for about 80% of all BC cases. BC patients who had bone metastases (BM) were more likely to have poor prognosis and bad quality of life, and earlier attention to patients at a high risk of BM was important. This study aimed to develop a predictive model based on machine learning to predict risk of BM in patients with IDC. Six different machine learning algorithms, including Logistic regression (LR), Naive Bayes classifiers (NBC), Decision tree (DT), Random Forest (RF), Gradient Boosting Machine (GBM), and Extreme gradient boosting (XGB), were used to build prediction models. The XGB model offered the best predictive performance among these 6 models in internal and external validation sets (AUC: 0.888, accuracy: 0.803, sensitivity: 0.801, and specificity: 0.837). Finally, an XGB model-based web predictor was developed to predict risk of BM in IDC patients, which may help physicians make personalized clinical decisions and treatment plans for IDC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Li, Wu, Tong, Li, Sun, Liu and Liu.)

To develop new compounds with high activity, broad spectrum and low-toxicity, 17 benzamides substituted with quinoline-linked 1,2,4-oxadiazole were designed using the splicing principle of active substructures and were synthesized. The biological activities were evaluated against 10 fungi, indicating that some of the synthetic compounds showed excellent fungicidal activities. For example, at 50 mg/L, the inhibitory activity of 13 p (3-Cl-4-Cl substituted, 86.1%) against Sclerotinia sclerotiorum was superior to that of quinoxyfen (77.8%), and the inhibitory activity of 13f (3-CF 3 substituted, 77.8%) was comparable to that of quinoxyfen. The fungicidal activities of 13 f and 13 p to Sclerotinia sclerotiorum were better than that of quinoxyfen (14.19 mg/L), with EC 50 of 6.67 mg/L and 5.17 mg/L, respectively. Furthermore, the acute toxicity of 13 p was 19.42 mg/L, classifying it as a low-toxic compound.

Objective: To develop a model based on machine learning to predict surgical site infection (SSI) risk in patients after lumbar spinal surgery (LSS)., Methods: Patients who developed postoperative SSI after LSS in the First Affiliated Hospital of Nanchang University between December 2010 and December 2019 were retrospectively reviewed. Preoperative and intraoperative variables, including age, diabetes mellitus, hypertension, body mass index, previous spinal surgery history, surgical duration, number of fused segments, blood loss, and surgical procedure were analyzed. Six machine learning algorithms-logistic regression, multilayer perceptron, decision tree, random forest, gradient boosting machine, and extreme gradient boosting-were used to build prediction models. The performance of the models was evaluated using the area under the curve, accuracy, precision, sensitivity, and F1 score. A web predictor was developed based on the best-performing model., Results: The study included 288 patients who underwent LSS, of whom 144 developed SSI and 144 did not develop SSI. The extreme gradient boosting model offers the best predictive performance among these 6 models (area under the curve = 0.923, accuracy = 0.860, precision = 0.900, sensitivity = 0.834, F1 score = 0.864). An extreme gradient boosting model-based web predictor was developed to predict SSI in patients after LSS., Conclusions: This study developed a machine learning model and a web predictor for predicting SSI in patients after LSS, which may help clinicians screen high-risk patients, provide personalized treatment, and reduce the incidence of SSI after LSS., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cell apoptosis plays an important role in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Heat shock protein 27 (HSP27), a member of the small heat shock protein (HSP) family, is induced by various stress factors and exerts protective role on cells. However, the role of HSP27 in brain injury after SAH needs to be further clarified. Here, we reported that HSP27 level of cerebrospinal fluid (CSF) is increased obviously at day 1 in patients with aneurysmal SAH (aSAH) and related to the grades of Hunt and Hess (HH), World Federation of Neurological Surgeons (WFNS), and Fisher score. In rat SAH model, HSP27 of CSF is first increased and then obviously declined; overexpression of HSP27, not knockdown of HSP27, attenuates SAH-induced neurological deficit and cell apoptosis in the basal cortex; and overexpression of HSP27 effectively suppresses SAH-elevated activation of mitogen-activated protein Kinase Kinase 4 (MKK4), the c-Jun N-terminal kinase (JNK), c-Jun, and caspase-3. In an in vitro hemolysate-damaged cortical neuron model, HSP27 65-90 peptide effectively inhibits hemolysate-induced neuron death. Furthermore, TAT-HSP27 65-90 peptide, a fusion peptide consisting of trans-activating regulatory protein (TAT) of HIV and HSP27 65-90 peptide, effectively attenuates SAH-induced neurological deficit and cell apoptosis in the basal cortex of rats. Altogether, our results suggest that TAT-HSP27 peptide improves neurologic deficits via reducing apoptosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhou, Sun, Wang, Li, Li, Yang, Yang, Yuan, Zhang, Sun and Han.)

Background: Ulcerative colitis (UC) is a multi-factor disease characterized by alternating remission periods and repeated occurrence. It has been shown that fecal microbiota transplantation (FMT) is an emerging and effective approach for UC treatment. Since most existing studies chose adults as donors for fecal microbiota, we conducted this study to determine the long-term efficacy and safety of the microbiota from young UC patient donors and illustrate its specific physiological effects., Methods: Thirty active UC patients were enrolled and FMT were administered with the first colonoscopy and two subsequent enema/transendoscopic enteral tubing (TET) practical regimens in The First Affiliated Hospital of Anhui Medical University in China. Disease activity and inflammatory biomarkers were assessed 6 weeks/over 1 year after treatment. The occurrence of adverse events was also recorded. The samples from blood and mucosa were collected to detect the changes of inflammatory biomarkers and cytokines. The composition of gut and oral microbiota were also sampled and sequenced to confirm the alteration of microbial composition., Results: Twenty-seven patients completed the treatment, among which 16 (59.3%) achieved efficacious clinical response and 11 (40.7%) clinical remission. Full Mayo score and calprotectin dropped significantly and remained stable over 1 year. FMT also significantly reduced the levels of C-reactive protein (CRP), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). The gut microbiota altered significantly with increased bacterial diversity and decreased metabolic diversity in responsive patients. The pro-inflammatory enterobacteria decreased after FMT and the abundance of Collinsella increased. Accordingly, the altered metabolic functions, including antigen synthesis, amino acids metabolism, short chain fatty acid production, and vitamin K synthesis of microbiota, were also corrected by FMT., Conclusion: Fecal microbiota transplantation seems to be safe and effective for active UC patients who are nonresponsive to mesalazine or prednisone in the long-term. FMT could efficiently downregulate pro-inflammatory cytokines to ameliorate the inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhang, Jin, Yang, Zhang, Ma, Guan, Sun and Chen.)

Background: Until now, Mendelian randomization (MR) studies have investigated the causal association of risk factors with Alzheimer's disease (AD) using large-scale AD genome-wide association studies (GWAS), GWAS by proxy (GWAX), and meta-analyses of GWAS and GWAX (GWAS+GWAX) datasets. However, it currently remains unclear about the consistency of MR estimates across these GWAS, GWAX, and GWAS+GWAX datasets., Methods: Here, we first selected 162 independent educational attainment genetic variants as the potential instrumental variables (N = 405,072). We then selected one AD GWAS dataset (N = 63,926), two AD GWAX datasets (N = 314,278 and 408,942), and three GWAS+GWAX datasets (N = 388,324, 455,258, and 472,868). Finally, we conducted a MR analysis to evaluate the impact of educational attainment on AD risk across these datasets. Meanwhile, we tested the genetic heterogeneity of educational attainment genetic variants across these datasets., Results: In AD GWAS dataset, MR analysis showed that each SD increase in years of schooling (about 3.6 years) was significantly associated with 29% reduced AD risk (OR=0.71, 95% CI: 0.60-0.84, and P=1.02E-04). In AD GWAX dataset, MR analysis highlighted that each SD increase in years of schooling significantly increased 84% AD risk (OR=1.84, 95% CI: 1.59-2.13, and P=4.66E-16). Meanwhile, MR analysis suggested the ambiguous findings in AD GWAS+GWAX datasets. Heterogeneity test indicated evidence of genetic heterogeneity in AD GWAS and GWAX datasets., Conclusions: We highlighted significant difference and genetic heterogeneity in clinically diagnosed AD GWAS and self-report proxy phenotype GWAX. Our MR findings are consistent with recent findings in AD genetic variants. Hence, the GWAX and GWAS+GWAX findings and MR findings from GWAX and GWAS+GWAX should be carefully interpreted and warrant further investigation using the AD GWAS dataset., (© 2022. The Author(s).)

Prostate cancer (PCa) is the major cause of cancer-related death in males; however, effective treatments to prevent aggressive progression remain an unmet need. We have previously demonstrated that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator that promotes PCa invasion. In the current study, we further investigate the therapeutic effects of an eNAMPT-neutralizing humanized monoclonal antibody (ALT-100 mAb) in preclinical PCa orthotopic xenograft models. We utilized human aggressive PCa cells (DU145 or PC3) for prostate implantation in SCID mice receiving weekly intraperitoneal injections of either ALT-100 mAb or IgG/PBS (control) for 12 weeks. Prostatic tumors and solid organs were examined for tumor growth, invasion, and metastasis and for biochemical and immunohistochemistry evidence of NFκB activation. ALT-100 mAb treatment significantly improved overall survival of SCID mice implanted with human PCa orthotopic prostate xenografts while inducing tumor necrosis, decreasing PCa proliferation and reducing local invasion and distal metastases. The ALT-100 mAb inhibits NFκB phosphorylation and signaling in PCa cells both in vitro and in vivo. This study demonstrates that eNAMPT neutralization effectively prevents human PCa aggressive progression in preclinical models, indicating its high potential to directly address the unmet need for an effective targeted therapy for patients with aggressive PCa.

Excessive glutamate leading to excitotoxicity worsens brain damage after SAH and contributes to long-term neurological deficits. The drug ifenprodil is a non-competitive antagonist of GluN1-GluN2B N-methyl-d-aspartate (NMDA) receptor, which mediates excitotoxic damage in vitro and in vivo. Here, we show that cerebrospinal fluid (CSF) glutamate level within 48 h was significantly elevated in aSAH patients who later developed poor outcome. In rat SAH model, ifenprodil can improve long-term sensorimotor and spatial learning deficits. Ifenprodil attenuates experimental SAH-induced neuronal death of basal cortex and hippocampal CA1 area, cellular and mitochondrial Ca 2+ overload of basal cortex, blood-brain barrier (BBB) damage, and cerebral edema of early brain injury. Using in vitro models, ifenprodil declines the high-concentration glutamate-mediated intracellular Ca 2+ increase and cell apoptosis in primary cortical neurons, reduces the high-concentration glutamate-elevated endothelial permeability in human brain microvascular endothelial cell (HBMEC). Altogether, our results suggest ifenprodil improves long-term neurologic deficits through antagonizing glutamate-induced excitotoxicity., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction and Importance: To describe an unusual case with a primary hepatic neuroendocrine tumour (PHNET) with multiple liver metastases., Case Presentation: We reported a 65-year-old woman with PHNET with multiple liver metastases. She was highly suspected of having primary liver cancer with multiple intrahepatic metastases before liver biopsy, but was diagnosed with PHNET with multiple liver metastases after histopathology and immunohistochemistry (IHC) examinations. The patient successfully underwent three times of transcatheter arterial chemoembolization (TACE), and is currently living in a good state without related complications., Clinical Discussion: Neuroendocrine tumors (NETs), also known as carcinoids or argyrophilic tumors, are very rare malignant tumors. The liver is the main metastasis site of NETs, but primary hepatic neuroendocrine tumors (PHNETs) are extremely rare. Histopathology and immunohistochemistry (IHC) examinations are still the main methods used for diagnosing NETs. There are no treatment guidelines for PHNETs, and surgical resection is generally the preferred treatment. For PHNET patients who are not suitable for surgery, TACE has been proven to be an effective alternative treatment that can effectively reduce the tumour burden and relieve symptoms, but the current evidence is still limited., Conclusion: The clinical diagnosis of PHNET still faces great challenges, imaging examinations often lead to misdiagnosis, and its diagnosis mainly depends on histopathology and immunohistochemical examinations. For PHNET patients who are not suitable for surgery, TACE may be an effective alternative therapy., (Copyright © 2021. Published by Elsevier Ltd.)

Prostate cancer is the second most common cause of cancer-related death in men in the United States and the fifth worldwide. Most prostate cancer arises as an androgen-dependent tumor but eventually progresses into castration-resistance prostate cancer, incurable by the current androgen deprivation therapy and chemotherapy. The development of immunotherapy in cancer treatment has brought an exciting era of antiprostate cancer therapy through antitumor immune responses. Prostate cancer is recognized as a poorly immunogenic tissue with immunological ignorance showing low levels of antigen-presenting process and cytotoxic T-cell activation, high levels of immune checkpoint molecules and immunosuppressive cytokines/chemokines, and recruitment of immunosuppressive cells. Immunotherapies for prostate cancer have been developed to activate the innate and adaptive immune responses, such as vaccines and adoptive CAR-T cells, or to inhibit immunosuppressive molecules, such as immune checkpoint inhibitors or antibodies. The U.S Food and Drug Administration has approved Sipuleucel-T for the treatment of asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC) and immune checkpoint inhibitor pembrolizumab for the treatment of all solid tumors, including prostate cancer, with impaired mismatch repair genes/microsatellite instability; however, the current clinical outcomes still need to be improved. As various immunosuppressive mechanisms coexist and cross-interact within the tumor microenvironment, different immunotherapy approaches may have to be combined and selected in a highly personalized way. It is hoped that this rapidly evolving field of immunotherapy will achieve successful treatment for mCRPC and will be applied to a wider range of prostate cancer patients., (© 2021 Wiley Periodicals LLC.)

Background: Although recent studies have focused on the use of metformin in treating ischemic stroke, there is little literature to support whether it can treat intracerebral hemorrhage (ICH). Therefore, this study is aimed at evaluating the possible effects of prestroke metformin (MET) on ICH patients with type 2 diabetes., Methods: From January 2010 to December 2019, all first-ever ICH patients with type 2 diabetes from our hospitals were included. All discharged patients would receive a one-time follow-up at 1 year after admission. Death, disability, and recurrence events were recorded., Results: We included 730 patients for analysis (the median age: 65 [IQR, 56-72] years and 57.7% was men). Of those patients, 281 (38.5%) had received MET before ICH (MET+), whereas 449 (61.5%) had not (MET-). MET (+) patients had a lower median baseline hematoma volume than did MET (-) patients (9.6 ml [IQR, 5.3-22.4 ml] vs. 14.7 ml [IQR, 7.9-28.6 ml]; P < 0.001). The inhospital mortality events were not significantly reduced in the MET (+) group compared with the MET (-) group (6.4% vs 8.9%, respectively; absolute difference, -2.5% [95% CI, -3.9% to -0.7%]; OR, 0.70 [95% CI, 0.39 to 1.27]; P = 0.22). The 1-year mortality events were not significantly reduced in the MET (+) group compared with the MET (-) group (14.1% vs 17.4%, respectively; absolute difference, -3.3% [95% CI, -5.1% to -1.8%]; OR, 0.73 [95% CI, 0.47 to 1.14]; P = 0.16). The 1-year disability events were not significantly reduced in the MET (+) group compared with the MET (-) group (28.4% vs 34.1%, respectively; absolute difference, -5.7% [95% CI, -8.2% to -3.3%]; OR, 0.77 [95% CI, 0.52 to 1.13]; P = 0.18). Finally, the recurrence rates in those two groups were not significantly different (MET [+] vs. MET [-]: 6.4% vs. 5.9%; absolute difference, 0.5% [95% CI, 0.2% to 1.3%]; OR, 1.08 [95% CI, 0.51 to 2.28]; P = 0.84)., Conclusions: Pre-ICH metformin use was not associated with inhospital mortality and 1-year prognosis in diabetic ICH patients., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2021 Wen-Jun Tu et al.)

Amyloid-beta (Aβ) plays a pivotal role in the pathogenesis of Alzheimer's disease (AD) and has been regarded as the main therapeutic target for AD. However, most of the Aβ-targeted clinical trials have not succeeded. Therefore, the Aβ-targeted therapeutic strategy on treating this complex disease needs to be re-evaluated. In this review, we analyzed the challenges and critical points of the current anti-Aβ therapeutic strategies. In addition to Aβ, multiple pathological events such as tau hyperphosphorylation, oxidative stress, and neuroinflammation, which are involved in AD pathogenesis and synergistically drive disease progression, could be important targets for AD treatment. Tertiary prevention strategies are needed for the successful management of AD due to its complex and dynamic pathogenesis. Systemic perspective addressing the disease pathogenesis within and outside the brain, as well as the multidomain intervention targeting risk factors and comorbidities, are important approaches for the therapeutic solutions of AD.

Objective: To evaluate the quality of the current foreign clinical practice guidelines (CPG) on obstetric venous thromboembolism (VTE), providing reference for standardizing the prevention and treatment of domestic VTE clinical practice. Methods: The GPGs for the management of obstetric VTE published abroad from inception to July 2020 were electronically searched. Two researchers independently evaluated the quality of the included guidelines in accordance with the internationally recognized guideline evaluation tool, AGREE Ⅱ. Results: A total of 12 guidelines, 2 recommendations and 1 consensus for obstetric VTE were included, covering 3 continents and 9 countries, and the published time span was 2009-2020. The standardized scores of the six domain (scope & purpose, stakeholder involvement, rigor of development, clarity of presentation, applicability and editorial independence) included in the guidelines were: 99.44%, 62.78%, 70.35%, 95.74%, 68.80% and 76.94% respectively, and the scores in each domain were ≥ 50.00%, indicating that the included CPGs were of good quality. Except for the domain scope & purpose, the ranges of the other five domains were ≥ 50.00%, suggesting that the quality of the CPGs differed significantly. Among the 15 included CPGs, 4 CPGs were level A (recommended), 11 CPGs were level B (recommended after being revised), and there was no CPG in level C (not recommended). The difference in the recommended content of obstetric VTE management mainly focused on the risk assessment, drug type, dosage and period. Conclusions: The overall quality of the CPGs for obstetric VTE management is high, while the quality of the CPGs varies greatly. In addition, there are differences in the recommended content of obstetric VTE management. More high-quality researches are required to provide evidence-based support for the improvement of the CPGs.

Arctigenin (ARG), a natural lignans compound isolated from Arctium lappa L. In this study, the anti-tumor effect of ARG on prostate cancer cell PC-3M and the mechanism of apoptosis and autophagy induced by phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway were discussed, and further confirmed by the joint treatment of ARG and PI3K inhibitor LY294002. Here, the effect of ARG on cell viability was evaluated in PC-3M cells by Cell Counting Kit-8 reagent (CCK-8) assay. After the treatment of ARG, colony formation assay was used to detect the anti-proliferation effect. Annexin V-fluoresceine isothiocyanate/propidium iodide (FITC/PI) kit and 4',6-diamidino-2-phenylindole (DAPI) staining were used to detect the apoptosis level, and cell cycle changes were analyzed by flow cytometry. The expression of autophagy was detected by acridine orange staining. In addition, the expression levels of apoptosis and autophagy-related proteins were analyzed by Western blot. The result showed that different concentrations of ARG inhibited the proliferation of PC-3M cells. DAPI staining and flow cytometry showed that ARG induced PC-3M cell apoptosis and arrested cell in G0/G1 phase. Acridine orange staining showed that ARG induced autophagy in PC-3M cells. Western blot experiments showed that ARG inhibited the expression of Bcl-2, promoted the expression of Bax and cleaved caspase-3. At the same time, the expression of autophagy-related proteins LC3B-II and Beclin-1 increased after ARG treatment, but P62 decreased. In addition, further studies have shown that treatment with LY294002 enhanced the effects of ARG on the expression of proteins associated with apoptosis and autophagy, indicating that ARG may induce apoptosis and autophagy through PI3K/Akt/mTOR pathway.

Immune response plays a vital role in the pathogenesis of neuropathic pain. Immune response-targeted therapy becomes an effective strategy for treating neuropathic pain. Licochalcone A (Lic-A) possesses anti-inflammatory and neuroprotective effects. However, the potential of Lic-A to attenuate neuropathic pain has not been well explored. To investigate the protective effect and evaluate the underlying mechanism of Lic-A against neuropathic pain in a rat model. Chronic constriction injury (CCI) surgery was employed in rats to establish neuropathic pain model. Rats were intraperitoneally administrated with Lic-A (1.25, 2.50 and 5.00 mg/kg) twice daily. Mechanical withdrawal threshold and thermal withdrawal latency were used to evaluate neuropathic pain. After administration, the lumbar spinal cord enlargement of rats was collected for ELISA, Western blot and immunofluorescence analysis. Mechanical withdrawal threshold and thermal withdrawal latency results showed that Lic-A significantly attenuated CCI-evoked neuropathic pain in dose-dependent manner. Lic-A administration also effectively blocked microglia activation. Moreover, Lic-A suppressed p38 phosphorylation and the release of inflammatory factors such as tumor necrosis factor-α, interleukin-1 and interleukin-6. Our findings provide evidence that Lic-A may have the potential to attenuate CCI-evoked neuropathic pain in rats by inhibiting microglia activation and inflammatory response.

Background & Aims: Mendelian randomization (MR) studies have reported the causal association between serum calcium levels and bone mineral density (BMD). The results showed that genetically increased serum calcium levels in individuals with normal calcium levels did not increase BMD and could even reduce BMD. However, whether there are differences in the association between serum calcium and BMD in different age strata remains unclear., Methods: We selected eight serum calcium genetic variants with genome-wide significance (P < 5.00E-08) as the potential instrumental variables. We conducted an MR analysis to evaluate the impact of serum calcium levels on total body BMD in five age strata, 0-15, 15-30, 30-45, 45-60, and ≥60 years, using large-scale serum calcium (61,079 individuals) and total body BMD genome-wide association study (66,628 individuals) datasets. For pleiotropy analysis, we used a manual method and four common statistical methods, namely the MR-Egger intercept, MR-PRESSO, heterogeneity, and Steiger filtering tests. For MR analysis, we selected four MR methods, namely inverse-variance weighted, weighted median, MR-Egger, and MR-PRESSO. In addition to the univariable MR analysis, we conducted a multivariate MR analysis taking into account the effect of serum parathyroid hormone levels., Results: Univariable MR analysis using the inverse-variance weighted method indicated that per 0.5-mg/dL increase (about 1 standard deviation) in serum calcium levels was statistically significantly associated with reduced total body BMD only in the ≥60 years stratum (effect estimate (beta) = -0.545, 95% confidence interval (CI): -0.892 to -0.198, P = 0.002). The weighted median regression (beta = -0.446, 95% CI: -0.821 to -0.094, P = 1.40E-02) and MR-PRESSO (beta = -0.545, 95% CI: -0.892 to -0.198, P = 0.022) MR methods further supported this suggestive association. The multivariable MR analysis also found a significant association between increased serum calcium levels and reduced total body BMD in the ≥60 years stratum (beta = -0.547, 95% CI: -0.934 to -0.16, P = 0.006)., Conclusions: Our results provide genetic evidence that increased serum calcium levels did not improve BMD in the general population and that the elevated serum calcium levels in generally healthy populations, especially in adults older than 60 years, may even reduce the BMD. Our results are comparable with those of recent MR findings., Competing Interests: Conflicts of interest The authors declare no competing financial interests., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Rationale: The myosin light chain kinase gene, MYLK, encodes three proteins via unique promoters, including the non-muscle isoform of myosin light chain kinase (nmMLCK), a cytoskeletal protein centrally involved in regulation of vascular integrity. As MYLK coding SNPs are associated with severe inflammatory disorders (asthma, acute respiratory distress syndrome (ARDS)), we explored clinically relevant inflammatory stimuli and promoter SNPs in nmMLCK promoter regulation., Methods: Full-length or serially deleted MYLK luciferase reporter promoter activities were measured in human lung endothelial cells (ECs). SNP-containing non-muscle MYLK (nmMYLK) DNA fragments were generated and nmMYLK promoter binding by transcription factors (TFs) detected by protein-DNA electrophoretic mobility shift assay (EMSA). Promoter demethylation was evaluated by 5-aza-2'-deoxycytidine (5-Aza). A preclinical mouse model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) was utilized for nmMLCK validation., Results: Lung EC levels of nmMLCK were significantly increased in LPS-challenged mice and LPS, tumor necrosis factor-α (TNF-α), 18% cyclic stretch (CS) and 5-Aza each significantly up-regulated EC nmMYLK promoter activities. EC exposure to FG-4592, a prolyl hydroxylase inhibitor that increases hypoxia-inducible factor (HIF) expression, increased nmMYLK promoter activity, confirmed by HIF1α/HIF2α silencing. nmMYLK promoter deletion studies identified distal inhibitory and proximal enhancing promoter regions as well as mechanical stretch-, LPS- and TNFα-inducible regions. Insertion of ARDS-associated SNPs (rs2700408, rs11714297) significantly increased nmMYLK promoter activity via increased transcription binding (glial cells missing homolog 1 (GCM1) and intestine-specific homeobox (ISX), respectively). Finally, the MYLK rs78755744 SNP (-261G/A), residing within a nmMYLK CpG island, significantly attenuated 5-Aza-induced promoter activity., Conclusion: These findings indicate nmMYLK transcriptional regulation by clinically relevant inflammatory factors and ARDS-associated nmMYLK promoter variants are consistent with nmMLCK as a therapeutic target in severe inflammatory disorders., (© 2021 The Author(s).)

Purpose: The project piloted a perioperative music listening program to explore the feasibility and acceptability of the use of music in a perioperative setting for female surgical patients in an academic hospital in Singapore. The aim was also to examine the most commonly chosen music genres, timing, and length of time listening to music for perioperative patients to assess the impact of music on patients' satisfaction, anxiety, and depression., Design: This was a quality improvement project., Methods: Music playlists developed by a music therapist were installed on three iPod Touch TM devices (Apple, Cupertino, CA). After obtaining consent, female patients undergoing elective gynecologic day surgery selected their preferred music from the playlists on the iPods to listen to during the preoperative and postoperative periods. Patients' anxiety and depression were measured using the Hospital Anxiety and Depression Scale and the three-level version of the EuroQol five-dimensional questionnaire. Patients' satisfaction with listening to music, duration, and chosen music genres were recorded., Findings: In the project, 135 patients listened to music during the preoperative period, and 70 patients chose to listen to music in the postoperative period. Patients were satisfied with the music listening program in both the preoperative (95.5%) and the postoperative (91.5%) periods. In the preoperative period, the most popular music genres were Disney songs (17.7%), classical music (11.6%), and the Piano Guys (7.5%). In the postoperative period, the most favorable music genres were classical music (26.3%), Disney songs (7.9%), and the Beatles (7.9%). This project suggests that music listening may be associated with patients' decreased anxiety and depression as measured by the three-level version of the EuroQol five-dimensional questionnaire questionnaire (P = .008)., Conclusions: Implementation of a music listening program in perioperative settings is feasible and accepted well by patients as evidenced by the high satisfaction scores. The project addressed patients' satisfaction, anxiety, and depression before and after elective surgery. The findings suggest that music listening is a safe, inexpensive, and effective intervention in perioperative settings., (Copyright © 2020 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)