Determining the maximum tolerated dose of paclitaxel combined with fixed dose of cisplatin for hyperthermic intraperitoneal chemotherapy in ovarian cancer: A multicenter phase I trial.

OBJECTIVE: To determine the maximum tolerated dose (MTD) of paclitaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered via hyperthermic intraperitoneal chemotherapy (HIPEC) to patients with ovarian cancer. METHODS: This multicenter Phase I trial employed a Bayesian Optimal Interval (BOIN) design. The MTD was determined to have a target dose-limiting toxicity (DLT) rate of 25%. The starting dose was 175 mg/m2. The Data and Safety Monitoring Board made decisions regarding dose escalation or de-escalation in increments of 25 mg/m2 for subsequent patient cohorts, up to a maximum sample size of 30 or 12 patients treated at a given dose. RESULTS: Twenty-one patients participated in this study. Among the three evaluable patients who received 150 mg/m2 paclitaxel, no DLTs were observed. Among the 12 evaluable patients who received 175 mg/m2 paclitaxel, two reported DLTs: one had grade 4 neutropenia and one had grade 4 anemia, neutropenia, and leukopenia. Four of the six evaluable patients who received 200 mg/m2 paclitaxel reported DLTs: one patient had grade 4 diarrhea, one had grade 3 kidney injury, and two had grade 4 anemia. The isotonic estimate of the DLT rate in the 175 mg/m2 dose group was 0.17 (95% confidence interval, 0.02-0.42), and this dose was selected as the MTD. CONCLUSION: Paclitaxel, when combined with a fixed dose of cisplatin (75 mg/m2), can be safely administered intraperitoneally at a dose of 175 mg/m2 in patients with ovarian cancer who received HIPEC (43 °C, 90 min) following cytoreductive surgery.

MSCs Deliver Hypoxia-Treated Mitochondria Reprogramming Acinar Metabolism to Alleviate Severe Acute Pancreatitis Injury.

Mitochondrial function impairment due to abnormal opening of the mitochondrial permeability transition pore (MPTP) is considered the central event in acute pancreatitis; however, therapeutic choices for this condition remain controversial. Mesenchymal stem cells (MSCs) are a family member of stem cells with immunomodulatory and anti-inflammatory capabilities that can mitigate damage in experimental pancreatitis. Here, it is shown that MSCs deliver hypoxia-treated functional mitochondria to damaged pancreatic acinar cells (PACs) via extracellular vesicles (EVs), which reverse the metabolic function of PACs, maintain ATP supply, and exhibit an excellent injury-inhibiting effect. Mechanistically, hypoxia inhibits superoxide accumulation in the mitochondria of MSCs and upregulates the membrane potential, which is internalized into PACs via EVs, thus, remodeling the metabolic state. In addition, cargocytes constructed via stem cell denucleation as mitochondrial vectors are shown to exert similar therapeutic effects to MSCs. These findings reveal an important mechanism underlying the role of mitochondria in MSC therapy and offer the possibility of applying mitochondrial therapy to patients with severe acute pancreatitis.

18F-FDG PET-CT for the prediction of mortality in patients with dermatomyositis and without malignant tumors: a pilot study.

Background: 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) is typically used to screen malignancy in patients with dermatomyositis (DM). The aim of this study was to investigate the value of using PET-CT in assessing the prognosis of patients with DM and without malignant tumors. Methods: A total of 62 patients with DM who underwent 18F-FDG PET-CT were enrolled in the retrospective cohort study. Clinical data and laboratory indicators were obtained. The muscle max standardized uptake value (SUVmax), splenic SUVmax, target-to-background ratio (TBR) of the aorta, pulmonary highest value (hv)/SUVmax, epicardial fat volume (EFV), and coronary artery calcium (CAC) were measured using 18F-FDG PET-CT. The follow-up was conducted until March 2021, and the endpoint was death from any cause. Univariable and multivariable Cox regression analyses were used to analyze prognostic factors. The survival curves were produced with the Kaplan-Meier method. Results: The median duration of follow-up was 36 [interquartile range (IQR), 14-53] months. The survival rates were 85.2% and 73.4% for 1 and 5 years, respectively. A total of 13 (21.0%) patients died during a median follow-up of 7 (IQR, 4-15.5) months. Compared with the survival group, the death group had significantly higher levels of C-reactive protein [CRP; median (IQR), 4.2 (3.0, 6.0) vs. 6.30 (3.7, 22.8)], hypertension [7 (14.3%) vs. 6 (46.2%)], interstitial lung disease [ILD; 26 (53.1%) vs. 12 (92.3%)], positive anti-Ro52 antibody [19 (38.8%) vs. 10 (76.9%)], pulmonary FDG uptake [median (IQR), 1.8 (1.5, 2.9) vs. 3.5 (2.0, 5.8)], CAC [1 (2.0%) vs. 4 (30.8%)], and EFV [median (IQR), 74.1 (44.8, 92.1) vs. 106.5 (75.0, 128.5)] (all P values <0.001). Univariable and multivariable Cox analyses identified high pulmonary FDG uptake [hazard ratio (HR), 7.59; 95% confidence interval (CI), 2.08-27.76; P=0.002] and high EFV (HR, 5.86; 95% CI, 1.77-19.42; P=0.004) as independent risk factors for mortality. The survival rate was significantly lower in patients with the concurrent presence of high pulmonary FDG uptake and high EFV. Conclusions: Pulmonary FDG uptake and EFV detected with PET-CT were independent risk factors for death in patients with DM and without malignant tumors. Patients with the concurrent presence of high pulmonary FDG uptake and high EFV had a worse prognosis compared with patients with 1 or neither of these two risk factors. Early treatment should be applied in patients with concurrent presence of high pulmonary FDG uptake and high EFV to improve the survival rate.

ROS Scavenging and inflammation-directed polydopamine nanoparticles regulate gut immunity and flora therapy in inflammatory bowel disease.

Dysfunction of the intestinal mucosal immune system and dysbiosis of the intestinal microflora can induce inflammatory bowel disease. However, drug-mediated clinical treatment remains a challenge due to its poor therapeutic efficacy and severe side effects. Herein, a ROS scavenging and inflammation-directed nanomedicine is designed and fabricated by coupling polydopamine nanoparticles with mCRAMP, an antimicrobial peptide, while wrapping macrophage membrane in the outer layer. The designed nanomedicine reduced the secretion of pro-inflammatory cytokines and elevate the expression of anti-inflammatory cytokine in vivo and in vitro inflammation models, demonstrating its significant ability of improving inflammatory responses. Importantly, the macrophage membrane encapsulated nanoparticles exhibit the obviously enhanced targeting performance in local inflamed tissues. Furthermore, the 16S rRNA sequencing of fecal microorganisms showed that probiotics increased and pathogenic bacteria were inhibited after oral delivery the nanomedicine, indicating that the designed nano platform played a significant role in optimizing intestinal microbiome. Taken together, the designed nanomedicine are not only easy to prepare and exhibit high biocompatibility, but also show the inflammatory targeting property, anti-inflammatory function and positive regulation of intestinal flora, thus providing a new idea for the intervention and treatment of colitis. STATEMENT OF SIGNIFICANCE: Inflammatory bowel disease (IBD), a chronic and intractable disease, may lead to colon cancer in severe cases without effective treatment. However, clinical drugs are largely ineffective owing to insufficient therapeutic efficacies and side effects. Herein, we constructed a biomimetic polydopamine nanoparticle for oral administration to treat the IBD by modulating mucosal immune homeostasis and optimizing intestinal microorganisms. In vitro and in vivo experiments showed that the designed nanomedicine not only exhibits the anti-inflammatory function and inflammatory targeting property but also positively regulate the gut microflora. Taken together, the designed nanomedicine combined immunoregulation and intestinal microecology modulation to significantly enhance the therapeutic effect on colitis in mice, thus providing a new approach for the clinical treatment of colitis.

Basic Fibroblast Growth Factor Promotes Mesenchymal Stem Cell Migration by Regulating Glycolysis-Dependent ß-Catenin Signaling.

Migration of mesenchymal stem cells (MSCs) to the site of injury is crucial in transplantation therapy. Studies have shown that cell migration is regulated by the cellular microenvironment and accompanied by changes in cellular metabolism. However, limited information is available about the relationship between MSC migration and cellular metabolism. Here, we show that basic fibroblast growth factor (bFGF) promotes the migration of MSCs with high levels of glycolysis and high expression of hexokinase 2 (HK2), a rate-limiting enzyme in glycolysis. The enhancement of glycolysis via the activation of HK2 expression promoted the migration of MSCs, whereas the inhibition of glycolysis, but not of oxidative phosphorylation, inhibited the bFGF-induced migration of these cells. Furthermore, bFGF enhanced glycolysis by increasing HK2 expression, which consequently promoted ß-catenin accumulation, and the inhibition of glycolysis inhibited the bFGF-induced accumulation of ß-catenin. When the accumulation of glycolytic intermediates was altered, phosphoenolpyruvate was found to be directly involved in the regulation of ß-catenin expression and activation, suggesting that bFGF regulates ß-catenin signaling through glycolytic intermediates. Moreover, transplantation with HK2-overexpressing MSCs significantly improved the effect of cell therapy on skull injury in rats. In conclusion, we propose a novel glycolysis-dependent ß-catenin signaling regulatory mechanism and provide an experimental and theoretical basis for the clinical application of MSCs.

Luteoloside Induces G0/G1 Phase Arrest of Neuroblastoma Cells by Targeting p38 MAPK.

Luteoloside has shown anti-inflammatory, antiviral, and antitumor properties. However, the effect and mechanism of luteoloside on neuroblastoma cells remain unknown. The proliferation of human neuroblastoma cells (SH-SY5Y and SK-N-AS) treated with different concentrations of luteoloside (0, 12.5, 25, and 50 µM) was detected by the MTT assay and colony formation assay. Cell apoptosis and cell cycle were examined by Hoechst staining and flow cytometry. A subcutaneous tumorigenesis model was established in nude mice to evaluate the effect of luteoloside on tumor growth in vivo. Bioinformatics, molecular docking techniques, and cellular thermal shift assays were utilized to predict the potential targets of luteoloside in neuroblastoma. The p38 MAPK inhibitor SB203580 was used to confirm the role of p38 MAPK. Luteoloside inhibited the proliferation of neuroblastoma cells in vitro and in vivo. Luteoloside slightly induced cellular G0/G1 phase arrest and reduced the expression levels of G0/G1 phase-related genes and the proteins cyclin D1, CDK4, and C-myc, which are downregulated by p38 MAPK pathways. Meanwhile, p38 was identified as the target of luteoloside, and inhibition of p38 MAPK reversed the inhibitory effect of luteoloside on neuroblastoma cells. Luteoloside is a potential anticancer drug for treating neuroblastoma by activating p38 MAPK.

Survival, treatment pattern, and treatment outcome in patients with cervical cancer metastatic to distant lymph nodes.

Background: Cervical cancer with nodal involvement beyond the pelvis was considered as distant nodal metastasis in the previous International Federation of Gynecology and Obstetrics staging system. With the improvement of cancer-directed therapies, some of these patients can receive curative treatment. Classifying them as distant metastasis may result in underestimation of their prognosis as well as undertreatment. However, limited research has been conducted on the survival and treatment pattern in distant lymphatic metastatic cervical cancer. Objective: To investigate the survival, treatment pattern, and treatment outcome of patients with cervical cancer metastasized to distant lymph nodes (DLN) beyond the pelvis. Methods: Patients with stage III-IV cervical cancer from 1988 to 2016 were identified using the Surveillance, Epidemiology, and End Results program. The cancer cause-specific survival (CSS) was analyzed using the Kaplan-Meier method, log-rank test, multivariable Cox proportional hazard regression, subgroup analysis, and propensity score-matched analysis. Results: Of 17783 patients with stage III-IV cervical cancer, patients with distant nodal disease beyond the pelvis (n=1883; included para-aortic lymph nodes metastasis) had superior survival compared to those with pelvic organ invasion or with distant organ(s) metastasis (5-year CSS, 32.3%, 26.3%, and 11.5%, respectively; adjusted P<0.001). The T stage significantly affected the survival of patients with positive DLN (5-year CSS for T1, T2, and T3: 47.3%, 37.0%, and 19.8%, respectively, adjusted P<0.01). For patients with positive DLN, combination radiotherapy (external beam radiotherapy [EBRT] with brachytherapy) prolonged CSS compared to EBRT alone (5-year CSS, 38.0% vs 21.7%; propensity score-adjusted HR, 0.60; 95% CI 0.51-0.72; P<0.001). Despite the superiority of combination radiotherapy, EBRT was the most frequently used treatment after 2004 (483/1214, 39.8%), while the utilization of combination radiotherapy declined from 37.8% (253/669) during 1988 through 2003 to 25.2% (306/1214) during 2004 through 2016. Conclusion: Patients with cervical cancer metastasized to DLN have favorable survival compared to those with pelvic organ invasion or with distant organ(s) metastasis. Their prognosis is significantly affected by local tumor burden and local treatment. Adequate and aggressive local radiotherapy, such as image-guided brachytherapy, can be considered for these patients to achieve better outcomes.

Detection of ovarian cancer using plasma cell-free DNA methylomes.

BACKGROUND: Ovarian cancer (OC) is a highly lethal gynecologic cancer, and it is hard to diagnose at an early stage. Clinically, there are no ovarian cancer-specific markers for early detection. Here, we demonstrate the use of cell-free DNA (cfDNA) methylomes to detect ovarian cancer, especially the early-stage OC. EXPERIMENTAL DESIGN: Plasma from 74 epithelial ovarian cancer patients, 86 healthy volunteers, and 20 patients with benign pelvic masses was collected. The cfDNA methylomes of these samples were generated by cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq). The differentially methylated regions (DMRs) were identified by the contrasts between tumor and non-tumor groups, and the discrimination performance was evaluated with the iterative training and testing method. RESULTS: The DMRs identified for cfDNA methylomes can well discriminate tumor groups and non-tumor groups (ROC values from 0.86 to 0.98). The late-stage top 300 DMRs are more late-stage-specific and failed to detect early-stage OC. However, the early-stage markers have the potential to discriminate all-stage OCs from non-tumor samples. CONCLUSIONS: This study demonstrates that cfDNA methylomes generated with cfMeDIP-seq could be used to identify OC-specific biomarkers for OC, especially early OC detection. To detect early-stage OC, the biomarkers should be directly identified from early OC plasma samples rather than mix-stage ones. Further exploration of DMRs from a k larger early-stage OC cohort is warranted.

Optimal Value for Serum Anti-PLA2R Antibody in Primary Membranous Nephropathy: A Multicenter Observational Study.

INTRODUCTION: Anti-phospholipase A2 receptor antibody (PLA2R-Ab) is highly specific for primary membranous nephropathy (PMN). Here, we compare the diagnostic value of different circulating PLA2R-Ab cutoff titers in multicenter cohorts, with particular focus on determining the optimal cutoff value for Chinese patients. METHODS: In total, 288 patients with PMN and 301 with other nephropathies were recruited retrospectively from five hospitals in China between September 2011 and October 2018. PLA2R-Ab in serum obtained at renal biopsy was determined by enzyme-linked immunosorbent assay. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and receiver operating characteristic (ROC) curve of PLA2R-Ab in diagnosing PMN were assessed. Diagnostic efficiency was evaluated by internal validation. RESULTS: The sensitivity, specificity, PPV, NPV, and Youden index for PMN diagnosis were 71%, 90%, 88%, 75%, and 0.61 at the cutoff of 3.8 RU/mL; 74%, 86%, 84%, 76%, and 0.60 at 2.7 RU/mL; 68%, 92%, 90%, 73%, and 0.60 at 5.2 RU/mL; 64%, 95%, 93%, 72%, and 0.59 at 9.0 RU/mL; 57%, 96%, 94%, 68%, and 0.54 at 14.0 RU/mL; 51%, 97%, 95%, 66%, and 0.49 at 20.0 RU/mL; 47%, 98%, 96%, 64%, and 0.45 at 40.0 RU/mL, respectively. The area under the ROC curve was 0.83. CONCLUSION: By comprehensively considering specificity and sensitivity, we show that 3.8 RU/mL is the optimal cutoff of PLA2R-Ab in Chinese PMN patients, with a sensitivity of 71% and a specificity of 90%. The cutoff values were 5.2 RU/mL and 9.0 RU/mL when the diagnostic specificity was increased to 92% and 95%, respectively.

Long Noncoding RNA RP11-115N4.1 Promotes Inflammatory Responses by Interacting With HNRNPH3 and Enhancing the Transcription of HSP70 in Unexplained Recurrent Spontaneous Abortion.

Background: Unexplained recurrent spontaneous abortion (URSA) is a common pregnancy complication and the etiology is unknown. URSA-associated lncRNAs are expected to be potential biomarkers for diagnosis, and might be related to the disease pathogenesis. Objective: To investigate differential lncRNAs in peripheral blood of non-pregnant URSA patients and matched healthy control women and to explore the possible mechanism of differential lncRNAs leading to URSA. Methods: We profiled lncRNAs expression in peripheral blood from 5 non-pregnant URSA patients and 5 matched healthy control women by lncRNA microarray analysis. Functions of URSA-associated lncRNAs were further investigated in vitro. Results: RP11-115N4.1 was identified as the most differentially expressed lncRNA which was highly upregulated in peripheral blood of non-pregnant URSA patients (P = 3.63E-07, Fold change = 2.96), and this dysregulation was further validated in approximately 26.67% additional patients (4/15). RP11-115N4.1 expression was detected in both lymphocytes and monocytes of human peripheral blood, and in vitro overexpression of RP11-115N4.1 decreased cell proliferation in K562 cells significantly. Furthermore, heat-shock HSP70 genes (HSPA1A and HSPA1B) were found to be significantly upregulated upon RP11-115N4.1 overexpression by transcriptome analysis (HSPA1A (P = 4.39E-08, Fold change = 4.17), HSPA1B (P = 2.26E-06, Fold change = 2.99)). RNA pull down and RNA immunoprecipitation assay (RIP) analysis demonstrated that RP11-115N4.1 bound to HNRNPH3 protein directly, which in turn activate heat-shock proteins (HSP70) analyzed by protein-protein interaction and HNRNPH3 knockdown assays. Most importantly, the high expression of HSP70 was also verified in the serum of URSA patients and the supernatant of K562 cells with RP11-115N4.1 activation, and HSP70 in supernatant can exacerbate inflammatory responses in monocytes by inducing IL-6, IL-1ß, and TNF-α and inhibit the migration of trophoblast cells, which might associate with URSA. Conclusion: Our results demonstrated that the activation of RP11-115N4.1 can significantly increase the protein level of HSP70 via binding to HNRNPH3, which may modulate the immune responses and related to URSA. Moreover, RP11-115N4.1 may be a novel etiological biomarker and a new therapeutic target for URSA.

Long noncoding RNA SOX2OT promotes pancreatic cancer cell migration and invasion through destabilizing FUS protein via ubiquitination.

Pancreatic cancer is a highly aggressive and lethal digestive system malignancy. Our previous studies revealed the correlation of high levels of lncRNA SOX2OT expression with patients' poor survival outcomes, the promoting role of SOX2OT in proliferation and cycle progression of pancreatic cancer cells, and the in vivo binding of SOX2OT to RNA binding protein FUS, which destabilized the protein expression of FUS. However, the mechanism of SOX2OT binding and inhibiting FUS protein stability remains unclear. In this study, we performed RNA pull-down, cycloheximide-chase, and ubiquitination assays to determine the effect of SOX2OT on FUS ubiquitination, and explored the specific regulatory mechanism of SOX2OT-FUS axis in pancreatic cancer cell migration, invasion, in vivo tumor growth, and metastasis through RNA sequencing. We found that SOX2OT binds to FUS through its 5' and 3' regions, resulting in FUS ubiquitination and degradation. The SOX2OT-FUS regulatory axis promotes migration, invasion, tumor growth, and metastasis ability of pancreatic cancer cells. The in-depth elaboration of the SOX2OT-FUS regulatory axis in pancreatic cancer may clarify the mechanism of action of SOX2OT and provide new ideas for pancreatic cancer treatment.

N6-Methyladenosine Associated Silencing of miR-193b Promotes Cervical Cancer Aggressiveness by Targeting CCND1.

OBJECTIVE: Cervical cancer is a frequently encountered gynecological malignancy as a major contributor to cancer-related deaths in women. This study focuses on how miR-193b promotes cervical cancer aggressiveness as well as the role of m6A in miR-193b silencing. METHODS: Cervical cancer samples and the matching adjacent normal cervical tissues were used to determine the significance of miR-193b in cervical cancer. The CCK-8 assay, cell cycle analysis, qRT-PCR, Western blot assay, IHC, RIP, and xenograft models were utilized to explore the impact of miR-193b in cervical cancer and how m6A regulates miR-193b expression. Luciferase reporter assays, qRT-PCR, and Western blotting were enlisted to study the interaction between miR-193b and CCND1. RESULTS: Our study suggested that lower miR-193b expressions were strongly linked to more advanced cervical cancer stages and the presence of deeper stromal invasion. miR-193b functions as a tumor suppressor that is regulated by m6A methylation in cervical tumors. METTL3 modulates miR-193b mature process in an m6A-dependent manner. Reintroduction of miR-193b profoundly inhibits tumorigenesis of cervical cancer cells both in vivo and in vitro through CCND1 targeting. CONCLUSIONS: m6A associated downregulation of miR-193b promotes cervical cancer aggressiveness by targeting CCND1.

Suppression of epithelial to mesenchymal transition markers in mouse lens by a Smad7-based recombinant protein.

Cataracts, a clouding of the eye lens, are a leading cause of visual impairment and are responsible for one of the most commonly performed surgical procedures worldwide. Although generally safe and effective, cataract surgery can lead to a secondary lens abnormality due to transition of lens epithelial cells to a mesenchymal phenotype (EMT) and opacification of the posterior lens capsular bag. Occurring in up to 40% of cataract cases over time, posterior capsule opacification (PCO) introduces additional treatment costs and reduced quality of life for patients. Studies have shown that PCO pathogenesis is driven in part by TGF-ß, signaling through the action of the family of Smad coactivators to effect changes in gene transcription. In the present study, we evaluated the ability of Smad-7, a well characterized inhibitor of TGF-ß -mediated Smad signaling, to suppress the EMT response in lens epithelial cells associated with PCO pathogenesis. Treatment of lens epithelial cells with a cell-permeable form of Smad7 variant resulted in suppressed expression of EMT markers such as alpha smooth muscle actin and fibronectin. A single application of cell-permeable Smad7 variant in the capsular bag of a mouse cataract surgery model resulted in suppression of gene transcripts encoding alpha smooth muscle actin and fibronectin. These results point to Smad7 as a promising biotherapeutic agent for prevention or substantial reduction in the incidence of PCO following cataract surgery.

HHLA2 predicts better survival and exhibits inhibited proliferation in epithelial ovarian cancer.

PURPOSE: The role of HHLA2, a new immune checkpoint ligand, is gradually being elucidated in various solid tumours. However, its role in ovarian cancer remains unclear; thus, its expression profile and clinical significance in ovarian cancer must be examined. METHODS: We performed immunohistochemistry to examine HHLA2 expression in 64 ovarian cancer tissues and 16 normal ovarian tissues. The relationships between HHLA2 expression and clinicopathological features, prognosis, and CD8+ tumour-infiltrating lymphocytes (TILs) in patients were analysed. Additionally, the Cancer Cell Line Encyclopedia database was used to analyse the correlation between HHLA2 expression and PD-L1 or B7x expression. Furthermore, the biological function of HHLA2 in ovarian cancer cells was initially explored. RESULTS: Only 17.2% of ovarian cancer patients showed HHLA2 expression, which was significantly associated with the differentiation of ovarian cancer cells (p = 0.027), and well-differentiated tumours expressed higher levels of HHLA2. The density of CD8+ TIL was associated with increased HHLA2 expression (p = 0.017), and the CD8+ TIL count was higher in the HHLA2-positive group than that in the HHLA2-negative group (p = 0.023). Moreover, multivariate analysis identified HHLA2 expression as an independent prognostic factor that predicted improved survival (p = 0.049; HR = 0.156; 95% CI = 0.025-0.992). Additionally, we also found that overexpressing HHLA2 inhibited the proliferation of ovarian cancer cells. CONCLUSION: HHLA2 is associated with tumour differentiation and high CD8+ TIL levels; and predicts improved survival in ovarian cancer. Along with previously reported findings that HHLA2 behaves as a co-stimulatory ligand, our study suggests that the loss of HHLA2 may contribute to the immunosuppressive microenvironment and progression of ovarian cancer.

Neuroprotective and Anti-inflammatory Effect of Tangeretin Against Cerebral Ischemia-Reperfusion Injury in Rats.

The neuro-inflammation is well known to be an inflammatory response in the brain tissue. Anti-inflammatory therapy in ischemia/reperfusion (I/R) pathogenesis is a potential therapeutic strategy for post-I/R injury. Currently, we made attempt to scrutinize the neuro-protective effect of tangeretin against I/R injury in the brain of experimental rats. I/R injury is induced in the brain via transient middle cerebral artery occlusion (2 h) and reperfusion (20 h). The infarction area, brain water content and neurofunctional parameters were also estimated. Inflammatory cytokines and brain injury markers were scrutinized at the end of the study. mRNA expression of interleukin 6 (IL-6), toll-like receptor-4 (TLR-4), interleukin 1ß (IL-1ß), tumor necrosis factor-α (TNF-α), interferon-γ (IFNG-γ), and transforming growth factor-ß1 (TGF-ß1) was estimated using the qRT-PCR. Tangeretin significantly (P < 0.001) decreased brain water content, infarct volume, neurological score, brain edema, and Evans blue leakage. Tangeretin significantly (P < 0.001) down-regulated the inflammatory and pro-inflammatory cytokines and oxidative stress parameters in the serum and brain tissue of experimental rats. qRT-PCR data demonstrated that rats treated with tangeretin could significantly (P < 0.001) suppress the IL-1ß, TLR-4 TNF-α, IFNG-γ, and IL-6 and boost the expression of TGF-ß1 compared with I/R injury rats. The result clearly showed tangeretin neuro-protective and anti-inflammatory effect against I/R injury in rats through suppressed inflammatory reaction.

Alteration of the abundance of Parvimonas micra in the gut along the adenoma-carcinoma sequence.

Parvimonas micra (P. micra) is reported to be associated with colorectal cancer (CRC). However, its association with colorectal adenoma (CRA) and its role in the initiation of colorectal tumors remain unknown. The present study aimed to clarify the relationship between P. micra and CRA and CRC by exploring the changes of P. micra abundance in an adenoma-carcinoma sequence in a new cohort and 4 public sequencing datasets. To investigate the alterations of P. micra abundance in the gut along the adenoma-carcinoma sequence, quantitative PCR (qPCR) was conducted to measure the relative abundance of P. micra in fecal samples from 277 subjects (128 patients with CRA, 66 patients with CRC and 83 healthy individuals, as controls) who underwent colonoscopy as outpatients. Then, the relative abundance of P. micra was analyzed in fecal samples from 596 subjects (185 healthy controls, 158 CRC, 253 CRA) in four public 16S rRNA sequencing datasets. The qPCR results demonstrated that the CRA group had an abundance of P. micra (P=0.2) similar to that of the healthy control group, while the CRC group had a significantly increased abundance (P=8.2×10-11). The level of P. micra effectively discriminated patients with CRC from healthy controls, while it poorly discriminated patients with CRA from healthy controls; with an area under the receiver operating characteristic curve of 0.867 for patients with CRC and 0.554 for patients with CRA. The same pattern of the alteration of P. micra abundance, which was low in healthy controls and patients with CRA but elevated in patients with CRC, was found in all four public sequencing datasets. These results suggested that P. micra was closely associated with, and may serve as a diagnostic marker for, CRC but not CRA. Moreover, it was indicated that P. micra may be an opportunistic pathogen of CRC, which may promote CRC development but serve a limited role in tumorigenesis.

N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine attenuates oxygen-glucose deprivation and reoxygenation-induced cerebral ischemia-reperfusion injury via regulation of microRNAs.

Cerebral ischemia-reperfusion injury is a common complication that occurs during stroke treatment. Increasingly, microRNAs have been found to participate in the modulation of neuron function; however, the role of microRNAs in cerebral ischemia-reperfusion injury remains unclear. We developed a mechanism of cerebral ischemia-reperfusion injury using a cellular model of oxygen-glucose deprivation and reoxygenation-induced injury in human neuroblastoma SH-SY5Y cells. We found that treatment of oxygen-glucose deprivation and reoxygenation promoted the apoptosis of SH-SY5Y cells. Analysis of microRNAs sequencing revealed that the expression of microRNA-27a-5p was induced, and microRNA-29b-3p expression was inhibited in neuroblastoma cells exposed to oxygen-glucose deprivation and reoxygenation. Either inhibition of microRNA-27a-5p or overexpression of microRNA-29b-3p mitigated oxygen-glucose deprivation and reoxygenation-induced cellular apoptosis. Bach1 was authenticated as a target gene of microRNA-27a-5p. Also, microRNA-27a-5p mediated the expression of Bach 1 along with its downstream signaling. N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine protected against oxygen-glucose deprivation and reoxygenation-induced apoptosis while decreasing miR-27a-5p expression and increasing microRNA-29b-3p expression. These results suggested that microRNA-27a-5p and microRNA-29b-3p may contribute to oxygen-glucose deprivation and reoxygenation-induced cellular injury. At the same time, N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine protects SH-SY5Y cells against oxygen-glucose deprivation and reoxygenation-induced injury partly through the inhibition of microRNA-27-a-5p and promotion of the Bach1/HO-1 signaling pathway.

A novel interspecies recombinant enterovirus (Enterovirus A120) isolated from a case of acute flaccid paralysis in China.

EV-A120 is a recently identified serotype of the enterovirus A species. Only one full-length genomic sequence is currently available in GenBank, and very few studies have been conducted on EV-A120 globally. Thus, additional information and research on EV-A120 are needed to explore its genetic characteristics, phylogeny, and relationship with enteroviral disease. In this study, we report the phylogenetic characteristics of a EV-A120 strain (Q0082/XZ/CHN/2000) from Tibet, China. The amino acid sequence similarity and nucleotide sequence similarity of the full-length genomic sequence of this EV-A120 strain and the EV-A120 prototype strain were 96.3% and 79.9%, respectively, showing an evolutionary trend. Recombination analysis found intraspecies recombination in the 5' -UTR, 2B, 2C, and 3D regions. Serum neutralization testing of the EV-A120 (Q0082) strain was also carried out. Low serum-positive rates and geometric mean titres (GMTs) indicated that the extent of EV-A120 transmission and exposure in the population was very limited compared with that in the outbreaks of EV-A71 and CV-A16 in China since 2008. The EV-A120 strain (Q0082) is non-temperature sensitive, indicating its potential to spread in the population. In summary, this study reports the full-length genomic sequence of EV-A120 and provides important information for its global molecular epidemiology.

Expression and clinical significance of Gal-3 and NFκB pathway-related factors in epithelial ovarian carcinoma.

OBJECTIVE: To explore the expression and clinical significance of Gal-3 and NFκB pathway related factors in epithelial ovarian carcinoma cells. METHODS: 99 histologic specimens of epithelial ovarian cancer and 20 normal ovarian histologic specimens were collected, and the expressions of Gal-3, IκB and p65 were detected by immunohistochemistry. Their relationship with clinical characteristics was analyzed. RESULTS: The expression of Gal-3 and p65 was negatively correlated with the overall survival rate (P<0.05), while the expression of IκB was positively correlated with the overall survival rate (P<0.05). Expression of Gal-3, p65 and IκB were found associated with EOC platinum resistance (P<0.05), and expression of Gal-3 and p65 correlated with pathologic grading (P<0.05). IκB and Gal-3 were associated with the recurrence of EOC (P<0.05). IκB may be related to clinical stage (P<0.05). Multivariate analysis results showed that abnormal expression of Gal-3 may be an independent prognostic risk factors for the drug resistance to platinum-based chemotherapy (95% CI=5.336~34.112, P<0.05). The expression of Gal-3, p65, and IκB can be clinical immunohistochemical indicators that determine the prognosis of EOC, but the amount of Gal-3 expression was related to the epithelial ovarian cancer's pathologic type and overall survival, which suggested that Gal-3 can be used as a prognostic factor in epithelial ovarian cancer. CONCLUSION: Targeted therapy of Gal-3 may become an effective potential new method against epithelial ovarian cancer.

A Case of Early Calciphylaxis Diagnosed by Bone Scan.

Calcium uremic aortic disease (calciphylaxis) has long been considered as a rare, life-threatening small vessel disease. The diagnosis of calciphylaxis depends mainly on clinical symptoms and high risk factors, and skin biopsy can be used to confirm the diagnosis. However, noninvasive testing methods are still the focus of exploration currently. There is increasing evidence that bone scintigraphy is helpful in the diagnosis of calciphylaxis, especially for assessing the involvement of muscles and internal organs. Here, we describe a pathology-proven case of calciphylaxis case and the corresponding imaging findings on Tc-99 m MDP bone scan imaging.