Aberrant expression of decoy receptor 3 in human breast cancer: relevance to lymphangiogenesis

AbstractBackgroundDecoy receptor 3 (DcR3), a decoy receptor against Fas ligand belonging to the tumor necrosis factor receptor superfamily, is overexpressed in some forms of cancer. It was recently reported that DcR3 could protect endothelial cells from apoptosis, implying a potential role in the development of vessels, whereas its role in the lymphangiogenesis remains unclear. In the present study, we studied the DcR3 expression and its relationship with the lymphatic microvessel density (LMVD) to investigate if it played a role in the lymph metastasis of human breast cancer.Materials and methodsReal-time polymerase chain reaction and immunohistochemistry were performed to measure the messenger RNA and protein expression of DcR3 in the breast cancer tissues, noncancerous counterparts, and axillary lymph node from 63 patients. LMVD in these specimens was assessed by counting the D2-40 labeled–microvessels. Furthermore, the correlations between DcR3 expression and LMVD and other clinicopathologic parameters were analyzed.ResultsDcR3 was overexpressed in the breast cancer tissue of 58 patients (92.1%) and was also expressed in vascular endothelial cells and tumor cells in the lymph nodes. LMVD in cancer tissue and lymph nodes were both positively correlated to the aberrant expression of DcR3.ConclusionsThe relevance between DcR3 overexpression and LMVD revealed the existence of possible links between DcR3 and lymphangiogenesis. Based on these findings, it is important to further explore the regulation of lymphangiogenesis operated by the reverse tumor necrosis factor signaling of DcR3

Association between systemic iron status and β-cell function and insulin sensitivity in patients with newly diagnosed type 2 diabetes

ObjectiveAbnormal iron metabolism is related to the risk of diabetes, but the underlying mechanism of this association remains uncertain. This study was conducted to evaluate the contributions of systemic iron status to β-cell function and insulin sensitivity of patients with newly diagnosed T2DM.MethodsA total of 162 patients with newly diagnosed T2DM and 162 healthy controls were enrolled in the study. Basic characteristics, biochemical indicators, and iron metabolism biomarkers, including serum iron (SI), ferritin (SF), transferrin (Trf), and transferrin saturation (TS), were collected. All patients underwent a 75 g oral glucose tolerance test. A series of parameters for assessing β-cell function and insulin sensitivity were calculated. The multivariate stepwise linear regression model was used to investigate the contributions of iron metabolism to β-cell function and insulin sensitivity.ResultsCompared with healthy controls, patients with newly diagnosed T2DM had significantly higher levels of SF. Among the diabetic patients, the SI and TS levels were higher, and the percentage of Trf levels below normal values was lower in men than in women. In all diabetic patients, SF was the independent risk factor associated with impaired β-cell function. Further stratification analysis showed that Trf was an independent protective factor for β-cell function in male patients, while SF was an independent risk factor for impaired β-cell function in female patients. However, systemic iron status did not affect insulin sensitivity.ConclusionElevated SF levels and decreased Trf levels had a profound effect on impaired β-cell function in Chinese patients with newly diagnosed T2DM

Effects of microencapsulated plant essential oils on growth performance, immunity, and intestinal health of weaned Tibetan piglets

IntroductionPlant essential oils (PEOs) have received significant attention in animal production due to their diverse beneficial properties and hold potential to alleviate weaning stress. However, PEOs effectiveness is often compromised by volatility and degradation. Microencapsulation can enhance the stability and control release rate of essential oils. Whether different microencapsulation techniques affect the effectiveness remain unknown. This study aimed to investigate the effects of PEOs coated by different microencapsulation techniques on growth performance, immunity, and intestinal health of weaned Tibetan piglets.MethodsA total of 120 Tibetan piglets, aged 30 days, were randomly divided into five groups with four replicates, each containing six piglets. The experimental period lasted for 32 days. The groups were fed different diets: a basal diet without antibiotics (NC), a basal diet supplemented with 10 mg/kg tylosin and 50 mg/kg colistin sulfate (PC), 300 mg/kg solidified PEO particles (SPEO), 300 mg/kg cold spray-coated PEO (CSPEO), or 300 mg/kg hot spray-coated PEO (HSPEO).ResultsThe results showed that supplementation with SPEO, CSPEO, or HSPEO led to a notable decrease in diarrhea incidence and feed to gain ratio, as well as duodenum lipopolysaccharide content, while simultaneously increase in average daily gain, interleukin-10 (IL-10) levels and the abundance of ileum Bifidobacterium compared with the NC group (p < 0.05). Supplementation with SPEO, CSPEO, or HSPEO significantly elevated serum immunoglobulin G (IgG) levels and concurrently reduced serum lipopolysaccharide and interferon γ levels compared with the NC and PC groups (p < 0.05). Serum insulin-like growth factor 1 (IGF-1) levels in the SPEO and HSPEO groups significantly increased compared with the NC group (p < 0.05). Additionally, CSPEO and HSPEO significantly reduced jejunum pH value (p < 0.05) compared with the NC and PC groups (p<0.05). Additionally, Supplementation with HSPEO significantly elevated levels of serum immunoglobulin M (IgM) and interleukin-4 (IL-4), abundance of ileum Lactobacillus, along with decreased serum interleukin-1 beta (IL-1β) levels compared with both the NC and PC groups.DiscussionOur findings suggest that different microencapsulation techniques affect the effectiveness. Dietary supplemented with PEOs, especially HSPEO, increased growth performance, improved immune function, and optimized gut microbiota composition of weaned piglets, making it a promising feed additive in piglet production

Association of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio with outcomes in stroke patients achieving successful recanalization by endovascular thrombectomy

ObjectiveSerum inflammatory biomarkers play crucial roles in the development of acute ischemic stroke (AIS). In this study, we explored the association between inflammatory biomarkers including platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and monocyte-to-lymphocyte ratio (MLR), and clinical outcomes in AIS patients who achieved successful recanalization.MethodsPatients with AIS who underwent endovascular thrombectomy (EVT) and achieved a modified thrombolysis in the cerebral infarction scale of 2b or 3 were screened from a prospective cohort at our institution between January 2013 and June 2021. Data on blood parameters and other baseline characteristics were collected. The functional outcome was an unfavorable outcome defined by a modified Rankin Scale of 3–6 at the 3-month follow up. Other clinical outcomes included symptomatic intracranial hemorrhage (sICH) and 3-month mortality. Multivariable logistic regression analysis was performed to evaluate the effects of PLR, NLR, and MLR on clinical outcomes.ResultsA total of 796 patients were enrolled, of which 89 (11.2%) developed sICH, 465 (58.4%) had unfavorable outcomes at 3 months, and 168 (12.1%) died at the 3-month follow up. After adjusting for confounding variables, a higher NLR (OR, 1.076; 95% confidence interval [CI], 1.037–1.117; p < 0.001) and PLR (OR, 1.001; 95%CI, 1.000–1.003; p = 0.045) were significantly associated with unfavorable outcomes, the area under the receiver operating characteristic curve of NLR and PLR was 0.622 and 0.564, respectively. However, NLR, PLR, and MLR were not independently associated with sICH and 3-month mortality (all adjusted p > 0.05).ConclusionOverall, our results indicate that higher PLR and NLR were independently associated with unfavorable functional outcomes in AIS patients with successful recanalization after EVT; however, the underlying mechanisms are yet to be elucidated

Role of the ISKpn element in mediating mgrB gene mutations in ST11 hypervirulent colistin-resistant Klebsiella pneumoniae

BackgroundColistin has emerged as a last-resort therapeutic against antibiotic-resistant bacterial infections, particularly those attributed to carbapenem-resistant Enterobacteriaceae (CRE) like CRKP. Yet, alarmingly, approximately 45% of multidrug-resistant Klebsiella pneumoniae strains now manifest resistance to colistin. Through our study, we discerned that the synergy between carbapenemase and IS elements amplifies resistance in Klebsiella pneumoniae, thereby narrowing the existing therapeutic avenues. This underscores the instrumental role of IS elements in enhancing colistin resistance through mgrB disruption.MethodsFrom 2021 to 2023, 127 colistin-resistant Klebsiella pneumoniae isolates underwent meticulous examination. We embarked on an exhaustive genetic probe, targeting genes associated with both plasmid-mediated mobile resistance-encompassing blaKPC, blaNDM, blaIMP, blaVIM, blaOXA-48-like, and mcr-1 to mcr-8-and chromosome-mediated resistance systems, including PhoP/Q, PmrA/B, and mgrB. PCR amplification revealed the presence of virulence-associated genes from the pLVPK plasmid, such as rmpA, rmpA2, iucA, iroB, and peg344. mgrB sequencing was delegated to Sangon Biotech, Shanghai, and the sequences procured were validated using BLAST. Our search for IS elements was navigated through the IS finder portal. Phenotypically, we harnessed broth microdilution (BMD) to ascertain the MICs of colistin. To sketch the clonal lineage of mgrB-mutated CoR-Kp isolates, sophisticated methodologies like MLST and PFGE were deployed. S1-PFGE unraveled the intrinsic plasmids in these isolates. Our battery of virulence assessment techniques ranged from the string test and capsular serotyping to the serum killing assay and the Galleria mellonella larval infection model.ResultsAmong the 127 analyzed isolates, 20 showed an enlarged mgrB PCR amplicon compared to wild-type strains. These emerged over a three-year period: three in 2021, thirteen in 2022, and four in 2023. Antimicrobial susceptibility tests revealed that these isolates consistently resisted several drugs, notably TCC, TZP, CAZ, and COL. Additionally, 85% resisted both DOX and TOB. The MICs for colistin across these strains ranged between 16 to 64 mg/L, with a median of 40 mg/L. From a genetic perspective, MLST unanimously categorized these mgrB-mutated CoR-hvKp isolates as ST11. PFGE further delineated them into six distinct clusters, with clusters A and D being predominant. This distribution suggests potential horizontal and clonal genetic transmission. Intriguingly, every mgrB-mutated CoR-hvKP isolate possessed at least two virulence genes akin to the pLVPK-like virulence plasmid, with iroB and rmpA2 standing out. Their virulence was empirically validated both in vitro and in vivo. A pivotal discovery was the identification of three distinct insertion sequence (IS) elements within or near the mgrB gene. These were:ISKpn26 in eleven isolates, mainly in cluster A, with various insertion sites including +74, +125, and an upstream −35.ISKpn14 in four isolates with insertions at +93, −35, and two upstream at −60.IS903B present in five isolates, marking positions like +74, +125, +116, and −35 in the promoter region. These diverse insertions, spanning six unique locations in or near the mgrB gene, underscore its remarkable adaptability.ConclusionOur exploration spotlights the ISKpn element’s paramount role in fostering mgrB gene mutations in ST11 hypervirulent colistin-resistant Klebsiella pneumoniae. Employing MLST and PFGE, we unearthed two primary genetic conduits: clonal and horizontal. A striking observation was the ubiquitous presence of the KPC carbapenemase gene in all the evaluated ST11 hypervirulent colistin-resistant Klebsiella pneumoniae strains, with a majority also harboring the NDM gene. The myriad mgrB gene insertion locales accentuate its flexibility and the overarching influence of IS elements, notably the pervasive IS5-like variants ISKpn26 and IS903B. Our revelations illuminate the escalating role of IS elements in antibiotic resistance within ST11 hypervirulent colistin-resistant Klebsiella pneumoniae, advocating for innovative interventions to counteract these burgeoning resistance paradigms given their profound ramifications for prevailing treatment modalities

Current Opinions on Optimal Management of Basilar Artery Occlusion: After the BEST of BASICS Survey

Background The best management of basilar artery occlusion (BAO) remains uncertain. The BASICS (Basilar Artery International Cooperation Study) and the BEST (Basilar Artery Occlusion Endovascular Intervention Versus Standard Medical Treatment) trials reported neutral results. We sought to understand physicians’ approaches to BAOs and whether further BAO randomized controlled trials were warranted. Methods We conducted an online international survey from January to March 2022 to stroke neurologists and neurointerventionalists. Survey questions were designed to examine clinical and imaging parameters under which clinicians would offer (or rescind) a patient with BAO to endovascular therapy (EVT) or best medical management versus enrollment into a randomized clinical trial. Results Of >3002 invited participants, 1245 responded (41.4% response rate) from 73 countries, including 54.7% stroke neurologists and 43.6% neurointerventionalists. More than 95% of respondents would offer EVT to patients with BAO, albeit in various clinical circumstances. There were 70.0% of respondents who indicated that the BASICS and BEST trials did not change their practice. Only 22.1% of respondents would perform EVT according to anterior circulation occlusion criteria. The selection of patients for BAO EVT by clinical severity, timing, and imaging modality differed according to geography, specialty, and country income level. Over 80% of respondents agreed that further randomized clinical trials for BAO were warranted. Moreover, 45.6% of respondents indicated they would find it acceptable to enroll all trial‐eligible patients into the medical arm of a BAO trial, whereas 26.3% would not enroll. Conclusion Most stroke physicians continue to believe in the efficacy of EVT in selected patients with BAO in spite of BEST and BASICS. There is no consensus on which selection criteria to use, and few clinicians would use anterior circulation occlusion criteria for BAOs. Further randomized clinical trials for BAO are warranted

Endovascular versus Medical Management of Acute Basilar Artery Occlusion: A Systematic Review and Meta-Analysis of the Randomized Controlled Trials

Background and Purpose The optimal management of patients with acute basilar artery occlusion (BAO) is uncertain. We aimed to evaluate the safety and efficacy of endovascular thrombectomy (EVT) compared to medical management (MM) for acute BAO through a meta-analysis of randomized controlled trials (RCTs). Methods We performed a systematic review and meta-analysis of RCTs of patients with acute BAO. We analyzed the pooled effect of EVT compared to MM on the primary outcome (modified Rankin Scale [mRS] of 0–3 at 3 months), secondary outcome (mRS 0–2 at 3 months), symptomatic intracranial hemorrhage (sICH), and 3-month mortality rates. For each study, effect sizes were computed as odds ratios (ORs) with random effects and Mantel-Haenszel weighting. Results Four RCTs met inclusion criteria including 988 patients. There were higher odds of mRS of 0-3 at 90 days in the EVT versus MM group (45.1% vs. 29.1%, OR 1.99, 95% confidence interval [CI] 1.04–3.80; P=0.04). Patients receiving EVT had a higher sICH compared to MM (5.4% vs. 0.8%, OR 7.89, 95% CI 4.10–15.19; P<0.01). Mortality was lower in the EVT group (35.5% vs. 45.1%, OR 0.64, 95% CI 0.42–0.99; P=0.05). In an analysis of two trials with BAO patients and National Institutes of Health Stroke Scale (NIHSS) <10, there was no difference in 90-day outcomes between EVT versus MM. Conclusion In this systematic review and meta-analysis, EVT was associated with favorable outcome and decreased mortality in patients with BAO up to 24 hours from stroke symptoms compared to MM. The treatment effect in BAO patients with NIHSS <10 was less certain. Further studies are of interest to evaluate the efficacy of EVT in basilar occlusion patients with milder symptoms