Efficacy and Safety of Anti-Programmed Cell Death Protein 1/Programmed Death-Ligand 1 Antibodies Plus Chemotherapy as First-Line Treatment for NSCLC in the People's Republic of China: a Systematic Review and Meta-Analysis.

Introduction: The available approved anticancer drugs for Chinese patients are relatively limited because of China's low participation rate in international clinical trials. Therefore, a focus on approved anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) drugs in China is needed. This study aims to assess the heterogeneity of anti-PD-1/PD-L1 antibodies manufactured in China (domestic PD-1/PD-L1) and overseas (imported PD-1/PD-L1) when combined with chemotherapy as the first-line treatment of NSCLC. Methods: A systematic search was performed using PubMed, EMBASE, and Cochrane Library of publications up to July 13, 2023. Meta-analysis was applied to compare the efficacy and safety profile between anti-PD-1/PD-L1 antibodies plus chemotherapy (PD-1/PD-L1+Chemo) and chemotherapy alone using STATA software. Pooled hazard ratios for progression-free survival and overall survival, odds ratios for objective response rate, and incidence rate of grade greater than or equal to three treatment-related adverse events with 95% confidence intervals were calculated in the domestic group and imported group by a random-effects model, and the heterogeneity between the two estimates was assessed. Results: There were 14 eligible clinical studies with a total of 3951 patients involved in this analysis, including eight studies of domestic PD-1/PD-L1+Chemo and six studies of imported PD-1/PD-L1+Chemo. The study revealed that there was no significant difference between domestic and imported PD-1/PD-L1+Chemo in overall survival (p = 0.80), progression-free survival (p = 0.53), and incidence rate of grade greater than or equal to three treatment-related adverse events (p = 0.10). Nevertheless, the objective response rate of imported PD-1/PD-L1+Chemo was significantly higher than that of domestic PD-1/PD-L1+Chemo (p = 0.03). Conclusions: Domestic anti-PD-1/PD-L1 antibodies plus chemotherapy were found to have comparable efficacy and safety to those combined with imported anti-PD-1/PD-L1 antibodies based on current evidence.

Propionic acid ameliorates cognitive function through immunomodulatory effects on Th17 cells in perioperative neurocognitive disorders.

Background: Elderly patients undergoing surgery are prone to cognitive decline known as perioperative neurocognitive disorders (PND). Several studies have shown that the microglial activation and the decrease of short-chain fatty acids (SCFAs) in gut induced by surgery may be related to the pathogenesis of PND. The purpose of this study was to determine whether microglia and short-chain fatty acids were involved in cognitive dysfunction in aged rats. Methods: Male wild-type Wistar rats aged 11-12 months were randomly divided into control group (Ctrl: Veh group), propionic acid group (Ctrl: PA group), exploratory laparotomy group (LP: Veh group) and propionic acid + exploratory laparotomy group (LP: PA group) according to whether exploratory laparotomy (LP) or PA pretreatment for 21 days was performed. The motor ability of the rats was evaluated by open field test on postoperative day 3 (POD3), and then the cognitive function was evaluated by Y-maze test and fear conditioning test. The expression of IL-1ß, IL-6, RORγt and IL-17A mRNA in hippocampus was detected by RT-qPCR, the expression of IL-17A and IL-17RA in hippocampus was detected by Western blot, and the activation of microglia was detected by immunofluorescence. Results: The PND rat model was successfully established by laparotomy. Compared with Ctrl: Veh group, the body weight of LP: Veh group decreased, the percentage of spontaneous alternations in Y maze decreased (P < 0.001), and the percentage of freezing time in contextual fear test decreased (P < 0.001). Surgery triggers neuroinflammation, manifested as the elevated levels of the inflammatory cytokines IL-1ß (P < 0.001) and IL-6 (P < 0.001), the increased expression of the transcription factor RORγt (P = 0.0181, POD1; P = 0.0073, POD5)and major inflammatory cytokines IL-17A (P = 0.0215, POD1; P = 0.0071, POD5), and the increased average fluorescence intensity of Iba1 (P < 0.001, POD1; P < 0.001, POD5). After PA preconditioning, the recovery of rats in LP: PA group was faster than that in LP: Veh group as the body weight lost on POD1 (P = 0.0148) was close to the baseline level on POD5 (P = 0.1846), and they performed better in behavioral tests. The levels of IL-1ß (P < 0.001) and IL-6 (P = 0.0035) inflammatory factors in hippocampus decreased on POD1 and the average fluorescence intensity of Iba1 decreased (P = 0.0024, POD1; P < 0.001, POD5), representing the neuroinflammation was significantly improved. Besides, the levels of RORγt mRNA (P = 0.0231, POD1; P = 0.0251, POD5) and IL-17A mRNA (P = 0.0208, POD1; P = 0.0071, POD5) in hippocampus as well as the expression of IL-17A (P = 0.0057, POD1; P < 0.001, POD5) and IL-17RA (P = 0.0388) decreased. Conclusion: PA pretreatment results in reduced postoperative neuroinflammation and improved cognitive function, potentially attributed to the regulatory effects of PA on Th17-mediated immune responses.

[Construction and Optimization of CD19 Chimeric Antigen Receptor T Cells Derived from C57BL/6J Mice].

OBJECTIVE: To explore the stimulation conditions, optimal culture time and infection time of C57BL/6J mice CD3+ T cells in vitro, so as to improve the infection efficiency of CD19 chimeric antigen receptor T cells (mCD19 CAR-T). METHODS: Purified C57BL/6J mice CD3+ T cells were cultured in anti-CD3/CD28 coated, anti-CD3 coated+soluble anti-CD28 and anti-CD3 coated, respectively. The cells were stimulated in above three conditions for 12 h and 24 h, following with 24 h, 48 h and 72 h incubation and then the number of cell clones was recorded. C57BL/6J mice CD3+ T cells were stimulated for 12 h, 24 h, and 36 h under the above three conditions, then interleukin (IL)-2 (100 U/ml) was added. The number of cell clones was recorded under microscope at 24 h, 48 h, and 72 h of culture. After 24 h of stimulation, CD3+ T cells derived from C57BL/6J mice were infected with retrovirus for 48 h to establish mCD19 CAR-T cells, and the percentage of GFP+ CAR-T cells was detected by flow cytometry. RESULTS: The infection efficiency of mCD19 CAR-T cells derived from C57BL/6J mice was only 5.23% under the optimized conditions of mCD19 CAR-T cells derived from BALB/c mice. The number of clones of C57BL/6J mice CD3+ T cells was the highest in anti-CD3 coated+soluble anti-CD28 group after stimulated for 24 h and followed cultured for 48 h. After 24 hours of stimulation under the above conditions and 48 hours of culture with IL-2, the number of T cell proliferating clones in the anti-CD3 coated+soluble anti-CD28 group was significantly increased compared with the same group without IL-2, and the infection efficiency of CAR-T cells in this group reached 17.63%±4.17%. CONCLUSION: The optimal conditions for constructing CAR-T cells from C57BL/6J mice CD3+ T cells are different from those of BABL/c mice. T cells stimulated by anti-CD3 coated+soluble anti-CD28+IL-2 can obtain mCD19 CAR-T cells with the highest efficiency after retrovirus infection.

Exosome-Transmitted miR-224-5p Promotes Colorectal Cancer Cell Proliferation via Targeting ULK2 in p53-Dependent Manner.

Objective: To investigate the role and molecular mechanism of exosomal miR-224-5p in colorectal cancer (CRC). Methods: The miR-224-5p expression in CRC patient tissues and cell-derived exosomes was measured by laser capture microdissection and qRT-PCR, respectively. Dual-luciferase reporter gene assay was used to determine the target gene of miR-224-5p. The protein expressions of p53 and unc-51 like kinase 2 (ULK2) in CRC cells were detected by western blot. Flow cytometry was used to detect cell cycle and apoptosis. Cell proliferation was measured by CCK8 and EdU assay. Results: The miR-224-5p expression was upregulated in CRC tissues and increased progressively with the rise of CRC stage. CRC cells secreted extracellular miR-224-5p mainly in an exosome-dependent manner, and then miR-224-5p could be transferred to surrounding tumor cells to regulate cell proliferation in the form of autocrine or paracrine. Moreover, ULK2 was characterized as a direct target of miR-224-5p and was downregulated in CRC tissues. Interestingly, ULK2 inhibited CRC cell proliferation in a p53-dependent manner. Furthermore, exosome-derived miR-224-5p partially reversed the proliferation regulation of ULK2 on CRC cells. Conclusion: Our findings demonstrate that exosome-transmitted miR-224-5p promotes p53-dependent cell proliferation by targeting ULK2 in CRC, which may offer promising targets for CRC prevention and therapy.

Neuron-secreted NLGN3 ameliorates ischemic brain injury via activating Gαi1/3-Akt signaling.

We here tested the potential activity and the underlying mechanisms of neuroligin-3 (NLGN3) against ischemia-reperfusion-induced neuronal cell injury. In SH-SY5Y neuronal cells and primary murine cortical neurons, NLGN3 activated Akt-mTOR and Erk signalings, and inhibited oxygen and glucose deprivation (OGD)/re-oxygenation (OGD/R)-induced cytotoxicity. Akt activation was required for NLGN3-induced neuroprotection. Gαi1/3 mediated NLGN3-induced downstream signaling activation. NLGN3-induced Akt-S6K1 activation was largely inhibited by Gαi1/3 silencing or knockout. Significantly, NLGN3-induced neuroprotection against OGD/R was almost abolished by Gαi1/3 silencing or knockout. In vivo, the middle cerebral artery occlusion (MCAO) procedure induced NLGN3 cleavage and secretion, and increased its expression and Akt activation in mouse brain tissues. ADAM10 (A Disintegrin and Metalloproteinase 10) inhibition blocked MCAO-induced NLGN3 cleavage and secretion, exacerbating ischemic brain injury in mice. Neuronal silencing of NLGN3 or Gαi1/3 in mice also inhibited Akt activation and intensified MCAO-induced ischemic brain injury. Conversely, neuronal overexpression of NLGN3 increased Akt activation and alleviated MCAO-induced ischemic brain injury. Together, NLGN3 activates Gαi1/3-Akt signaling to protect neuronal cells from ischemia-reperfusion injury.

Distribution of Metallic Elements in Four Group Components of High-Temperature Coal Tar Pitch.

The metallic elements in high-temperature coal tar pitch (HCTP) will affect the properties of carbon materials produced from the HCTP. The study on the metallic elements in HCTP is essential for the quality improvement of its derived carbon materials. In this paper, the content of 15 metallic elements in HCTP and its four group components, including n-heptane-soluble substance (HS), n-heptane-insoluble-toluene-soluble substance (HI-TS), toluene-insoluble-quinoline-soluble substance (TI-QS), and quinoline-insoluble substance (QI), was determined. The results show that the content of Na, Ca, Fe, Mg, Zn, K, Pb, and Al is more than 100 ppm and is much higher than that of other metallic elements. The content of Ni, V, Cr, Mo, Sb, Cu, and Mn ranges from 0 to 50 ppm. By mass calculation of the contents of four group components in HCTP, it can be concluded that Na and Fe are randomly distributed in the group components. Al, Zn, Pb, V, and Mn are mainly distributed in the inorganic form in the QI component. Ca, Mg, K, Ni, Cr, Mo, Sb, and Cu are mainly distributed in the small molecular group components such as HS and HI-TS.

Lipocalin-2 inhibits pancreatic cancer stemness via the AKT/c-Jun pathway.

Cancer stem cells (CSCs) are involved in cancer recurrence and metastasis owing to their self-renewal properties and drug-resistance capacity. Lipocalin-2 (Lcn2) of the lipocalin superfamily is highly expressed in pancreatic cancer. Nevertheless, reports on the involvement of Lcn2 in the regulation of pancreatic CSC properties are scant. This study is purposed to investigate whether Lcn2 plays a crucial role in CSC renewal and stemness maintenance in pancreatic carcinoma. Immunohistochemistry results of tumor tissue chips together with Gene Expression Omnibus sequencing files confirmed that Lcn2 is highly expressed in pancreatic carcinoma compared with that in normal tissues. The exogenous expression of Lcn2 attenuated CSC-associated SOX2, CD44, and EpCAM expression and suppressed sarcosphere formation and tumorigenesis in the pancreatic carcinoma cell line PANC-1, which showed low expression of Lcn2. However, Lcn2 knockout in BxPC-3 cell line, which presented high Lcn2 expression, promoted CSC stemness, further enhancing sarcosphere formation and tumorigenesis. Moreover, Lcn2 was found to regulate stemness in pancreatic cancer depending on the activation of AKT and c-Jun. Lcn2 suppresses stemness properties in pancreatic carcinoma by activating the AKT-c-Jun pathway, and thus, it may be a novel candidate to suppress the stemness of pancreatic cancer. This study provides a new insight into disease progression.

The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress glioblastoma progression.

BACKGROUND: Elucidation of the post-transcriptional modification has led to novel strategies to treat intractable tumors, especially glioblastoma (GBM). The ubiquitin-proteasome system (UPS) mediates a reversible, stringent and stepwise post-translational modification which is closely associated with malignant processes of GBM. To this end, developing novel therapeutic approaches to target the UPS may contribute to the treatment of this disease. This study aimed to screen the vital and aberrantly regulated component of the UPS in GBM. Based on the molecular identification, functional characterization, and mechanism investigation, we sought to elaborate a novel therapeutic strategy to target this vital factor to combat GBM. METHODS: We combined glioma datasets and human patient samples to screen and identify aberrantly regulated E3 ubiquitin ligase. Multidimensional database analysis and molecular and functional experiments in vivo and in vitro were used to evaluate the roles of HECT, UBA and WWE domain-containing E3 ubiquitin ligase 1 (HUWE1) in GBM. dCas9 synergistic activation mediator system and recombinant adeno-associated virus (rAAV) were used to endogenously overexpress full-length HUWE1 in vitro and in glioma orthotopic xenografts. RESULTS: Low expression of HUWE1 was closely associated with worse prognosis of GBM patients. The ubiquitination and subsequent degradation of N-Myc mediated by HUWE1, leading to the inactivation of downstream Delta-like 1 (DLL1)-NOTCH1 signaling pathways, inhibited the proliferation, invasion, and migration of GBM cells in vitro and in vivo. A rAAV dual-vector system for packaging and delivery of dCas9-VP64 was used to augment endogenous HUWE1 expression in vivo and showed an antitumor activity in glioma orthotopic xenografts. CONCLUSIONS: The E3 ubiquitin ligase HUWE1 acts through the N-Myc-DLL1-NOTCH1 signaling axis to suppress GBM progression. Antitumor activity of rAAV dual-vector delivering dCas9-HUWE1 system uncovers a promising therapeutic strategy for GBM.

Interleukin-6-white matter network differences explained the susceptibility to depression after stressful life events.

BACKGROUND: Stressful life events (SLEs) are well-established proximal predictors of the onset of depression. However, the fundamental causes of interindividual differences in depression outcomes are poorly understood. This study addressed this depression susceptibility mechanism using a well-powered sample of adults living in China. METHODS: Healthy participants with SLEs (n = 185; mean = 47.51 years, 49.73% female), drawn from a longitudinal study on the development of depression, underwent diffusion tensor imaging, interleukin-6 (IL-6) level measurement, and trimonthly standardized clinical and scale evaluations within a two-year period. RESULTS: Receiver operating characteristic analyses indicated that reduced feeder connection and HIP.R nodal efficiency improved the predictive accuracy of post-SLEs depression (ORfeeder = 0.623, AUC = 0.869, P < 0.001; ORHIP = 0.459, AUC = 0.855, P < 0.001). The successfully established path analysis model confirmed the significant partial effect of SLEs-IL-6-white matter (WM) network differences-depression (onset and severity) (x2/8 = 1.453, goodness-of-fit [GFI] = 0.935, standard root-mean-square error of approximation [SRMR] = 0.024). Females, individuals with lower exercise frequency (EF) or annual household income (AHI) were more likely to have higher IL-6 level after SLEs (ßint-female⁎SLEs = -0.420, P < 0.001; ßint-exercise⁎SLEs = -0.412, P < 0.001; ßint-income⁎SLEs = -0.302, P = 0.005). LIMITATIONS: The sample size was restricted due to the limited incidence rate and prospective follow-up design. CONCLUSIONS: Our results suggested that among healthy adults after SLEs, those who exhibited abnormal IL-6-WM differences were susceptible to developing depression. Females, lower AHI or EF might account for an increased risk of developing these abnormal IL-6-WM differences.

Neuron secrete exosomes containing miR-9-5p to promote polarization of M1 microglia in depression.

BACKGROUND: Neuroinflammation is an important component mechanism in the development of depression. Exosomal transfer of MDD-associated microRNAs (miRNAs) from neurons to microglia might exacerbate neuronal cell inflammatory injury. RESULTS: By sequence identification, we found significantly higher miR-9-5p expression levels in serum exosomes from MDD patients than healthy control (HC) subjects. Then, in cultured cell model, we observed that BV2 microglial cells internalized PC12 neuron cell-derived exosomes while successfully transferring miR-9-5p. MiR-9-5p promoted M1 polarization in microglia and led to over releasing of proinflammatory cytokines, such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), which exacerbated neurological damage. Furthermore, we identified suppressor of cytokine signaling 2 (SOCS2) as a direct target of miR-9-5p. Overexpression of miR-9-5p suppressed SOCS2 expression and reactivated SOCS2-repressed Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways. Consistently, we confirmed that adeno-associated virus (AAV)-mediated overexpression of miR-9-5p polarized microglia toward the M1 phenotype and exacerbated depressive symptoms in chronic unpredictable mild stress (CUMS) mouse mode. CONCLUSION: MiR-9-5p was transferred from neurons to microglia in an exosomal way, leading to M1 polarization of microglia and further neuronal injury. The expression and secretion of miR-9-5p might be novel therapeutic targets for MDD.

Glucagon-like peptide-1 receptor activation by liraglutide promotes breast cancer through NOX4/ROS/VEGF pathway.

AIMS: Scientific evidence imply the strong correlation between diabetes and breast cancer. Glucagon-like peptide-1 (GLP-1) and its analogue liraglutide, have been widely used for diabetes treatment. However, the role of GLP-1 receptor (GLP-1R) in breast cancer requires further elucidation. This study aimed to investigate the risk and the molecular mechanisms of liraglutide using in breast cancer. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction, western blot or immunohistochemistry were used to detect the expressions of GLP-1R, NADPH oxidase 4 (NOX4) and vascular endothelial growth factor (VEGF) in human triple negative breast cancer (TNBC) cells (MDA-MB-231 and MDA-MB-468) and tissues derived from BALB/cfC3H mouse bearing 4T1 cells inoculation. Cell proliferation and migration was detected using the Cell Counting Kit-8, adenosine triphosphate assay, and transwell assay, respectively. Flow cytometry was used to measure the level of reactive oxygen species (ROS). KEY FINDINGS: We found that the expression of GLP-1R increased after liraglutide treatment in breast cancer cells and the transplanted tumors. Liraglutide, at a slightly higher concentration, accelerated breast cancer progress in vitro (100 nM) and in vivo (400µg/kg) through the NOX4/ROS/VEGF signal pathway after activating GLP-1R. The GLP-1R inhibitor, Exendin (9-39), significantly inhibited the effect of liraglutide, inducing a reversed function of GLP-1R activation. SIGNIFICANCE: Our study illustrated that in an approximately toxicology context, liraglutide may promote the malignant progression of TNBC. The dosage and the phenotype of the breast cancer should be considered as important factors for the rational administration of antidiabetic drugs, especially that of liraglutide in breast cancer patients.

Alternatones A and B, two polyketides possessing novel skeletons from entophyte Alternaria alternate L-10.

On our ongoing searching for bioactive natural products derived from entophytes, two polyketides possessing novel skeletons, alternatones A-B (1-2), were identified from the culture of Alternaria alternate L-10. Their structures were established by a combination of spectroscopic and single-crystal X-ray diffraction with Cu Ka radiation. Alternatone A (1) exhibited cytotoxic activity against human hepatoma carcinoma HepG-2 cell line. The putative biosynthetic pathways for compounds 1-2 were also proposed.

Reversal of Chemotherapy Resistance to Cisplatin in NSCLC by miRNA-195-5p via Targeting the FGF2 Gene.

OBJECTIVE: To explore the mechanism of miR-195-5p in the pathogenesis non-small cell lung cancer (NSCLC) and cisplatin resistance. METHODS: The function of miR-195-5p in NSCLC and cisplatin resistance were determined by MTT, scratch assay, transwell assay, and nude mice xenograft experiments. miR-195-5p target gene was identified by dual-luciferase reporter assays and real-time PCR analysis. RESULTS: miR-195-5p content was lower in A549/DDP than that in A549 cells, with reduced chemotherapy sensitivity and increased cell invasion and migration ability. The loss-of-function and gain-of-function assays illustrated that miR-195-5p might have increased the chemosensitivity to cisplatin in the A549/DDP cells and decreased cell migration and invasion. FGF2 is a negatively correlated action target of miR-195-5p. miR-195-5p might affect EMT by inhibiting FGF2. Overexpression of FGF2 resulted in enhanced cisplatin resistance in the cells, while miR-195-5p might have reversed this resistance. CONCLUSION: Overall, miR-195-5p might target FGF2 to reduce cisplatin resistance in A549/DDP cells and enhance chemosensitivity.

Short-term outcomes of radiofrequency ablation for hepatocellular carcinoma using cone-beam computed tomography for planning and image guidance.

BACKGROUND: Percutaneous radiofrequency ablation (RFA) is an effective treatment for unresectable hepatocellular carcinoma (HCC) and a minimally invasive alternative to hepatectomy for treating tumour recurrence. RFA is often performed using contrast-enhanced computed tomography (CECT) and/or ultrasonography. In recent years, angiographic systems with flat panel image detectors and advanced image reconstruction algorithms have broadened the clinical applications of cone-beam computed tomography (CBCT), including RFA. Several studies have shown the effectiveness of using CBCT for immediate treatment assessments and follow-ups. AIM: To assess the treatment response to RFA for HCC using CBCT. METHODS: Forty-eight patients (44 men; aged 37-89 years) with solitary HCC [median size: 3.2 (1.2-6.6) cm] underwent RFA and were followed for 25.6 (median; 13.5-35.2) mo. Image fusion of CBCT and pre-operative CECT or magnetic resonance imaging (MRI) was used for tumour segmentation and needle path and ablation zone planning. Real-time image guidance was provided by overlaying the three-dimensional image of the tumour and needle path on the fluoroscopy image. Treatment response was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Disease progression, death, time to progression (TTP), and overall survival (OS) were recorded. Kaplan-Meier and Cox regression analyses were performed. RESULTS: Initial post-RFA CECT/MRI showed 38 cases of CR (79.2%), 10 of PR (20.8%), 0 of SD, and 0 of PD, which strongly correlated with the planning estimation (42 CR, 87.5%; 6 PR, 12.5%; 0 SD; and 0 PD; accuracy: 91.7%, P < 0.01). Ten (20.8%) patients died, and disease progression occurred in 31 (35.4%, median TTP: 12.8 mo) patients, resulting in 12-, 24-, and 35-mo OS rates of 100%, 81.2%, and 72.2%, respectively, and progression-free survival (PFS) rates of 54.2%, 37.1%, and 37.1%, respectively. The median dose-area product of the procedures was 79.05 Gy*cm2 (range 40.95-146.24 Gy*cm2), and the median effective dose was 10.27 mSv (range 5.32-19.01 mSv). Tumour size < 2 cm (P = 0.008) was a significant factor for OS, while age (P = 0.001), tumour size < 2 cm (P < 0.001), tumour stage (P = 0.010), and initial treatment response (P = 0.003) were significant factors for PFS. CONCLUSION: Reliable RFA treatment planning and satisfactory outcomes can be achieved with CBCT.

Common variation of the NSD1 gene is associated with susceptibility to Hirschsprung's disease in Chinese Han population.

BACKGROUND: Hirschsprung's disease (HSCR) is the most common congenital cause of intestinal obstruction in children. Sotos syndrome (SoS) is an overgrowth disorder with constipation and sometimes accompanied by HSCR. NSD1 gene mutation is the main cause of SoS. We aimed to investigate association of NSD1 common single nucleotide polymorphisms (SNPs) with HSCR susceptibility in Chinese Han population. METHOD: We genotyped 15 SNPs encompassing NSD1 gene region in 420 HSCR patients and 1665 controls on Fludigm EP1 platform. Association analysis was performed between cases and controls. RESULT: Rs244709 was the most associated SNP with HSCR susceptibility of the sample set (PAllelic = 9.69 × 10-5, OR = 1.37, 95% CI: 1.17-1.61). Gender stratification analysis revealed that NSD1 SNPs were associated with HSCR in males, but not in females. The nonsynonymous coding SNP rs28932178 in NSD1 exon 5 represented the most significant signal in males (PAllelic = 6.43 × 10-5, OR = 1.42, 95% CI: 1.20-1.69). The associated SNPs were expression quantitative trait loci (eQTLs) of nearby genes in multiple tissues. NSD1 expression levels were higher in aganglionic colon tissues than ganglionic tissues (P = 3.00 × 10-6). CONCLUSION: NSD1 variation conferred risk to HSCR in males, indicating SoS and HSCR may share common genetic factors. IMPACT: This is the first study to reveal that NSD1 variation conferred risk to Hirschsprung's disease susceptibility in males of Chinese Han population, indicating Sotos syndrome and Hirschsprung's disease may share some common genetic background. This study indicates more attention should be paid to the symptom of constipation in patients with Sotos syndrome. Our results raise questions about the role of NSD1 in the development of enteric nervous system and the pathogenesis of Hirschsprung's disease.

Lipocalin2 promotes cell proliferation and migration in ovarian cancer through activation of the ERK/GSK3ß/ß-catenin signaling pathway.

Lipocalin2 (Lcn2) has been shown to be a vital regulator of tumorigenesis in a variety of different cancers. However, its expression patterns and possible roles in ovarian cancer remain obscure. The aim of this study was to investigate the expression of Lcn2 in ovarian cancer cells and to determine any potential association between Lcn2 and ovarian tumor development and cancer progression. Our results indicated that Lcn2 was upregulated in tumor tissue from ovarian cancer patients as well as in three ovarian cancer cell lines compared to normal tissues and cells. Overexpression of Lcn2 promoted both cell proliferation and migration in ovarian cancer cells. Conversely, knockdown of Lcn2 in cell lines suppressed both migration and proliferation. Moreover, upregulation of Lcn2 contributed to tumor growth in nude mice in vivo. Mechanistically, Lcn2 was found to lead to tumor progression in ovarian cancer cells through activation of the ERK/GSK3ß/ß-catenin signaling pathway. In summary, Lcn2 promotes cell proliferation and migration in ovarian cancer through activation of the ERK/GSK3ß/ß-catenin signaling pathway, suggesting that Lcn2 might be a novel therapeutic target for ovarian cancer.

Role of the initial degree of anaemia and treatment model in the prognosis of gastric cancer patients treated by chemotherapy: a retrospective analysis.

BACKGROUND: Anaemia is highly prevalent in gastric cancer (GC) patients. The role of initial haemoglobin levels in predicting the prognosis of GC patients treated by chemotherapy has not been well determined. Our present study aims to evaluate the relationship between the degree of anaemia and the overall survival (OS) and progression-free survival (PFS) of patients with GC. METHODS: Our retrospective study enrolled 598 patients who were treated with chemotherapy when the recurrent or metastatic GCs were unsuitable for surgical resection. Univariate and multivariate analyses were performed to identify risk factors that had the potential to affect patient prognosis. Additionally, the relationship between clinicopathological characteristics, including treatment method, and degree of cancer-related reduction in haemoglobin was further analysed. RESULTS: Our results revealed that patients with HBini level ≤ 80 g/L had a trend toward a shortened median OS and PFS (p = 0.009 and p = 0.049, respectively). Interestingly, we also found that HBdec ≥ 30 g/L was associated with a significantly shortened median OS and PFS (p = 0.039 and p = 0.001, respectively). Multivariate analysis showed that HBini levels ≤80 g/L could be used as an independent prognostic factor for recurrent and metastatic GC. More importantly, HBdec ≥ 30 g/L and treatment response were also significantly associated with OS and PFS. Furthermore, the degree of haemoglobin decrease was associated with chemotherapy including platinum and the number of chemotherapy cycles. CONCLUSION: Our study concludes that the initial degree of anaemia and a decrease in haemoglobin of ≥30 g/L can serve as biomarkers to predict prognosis in recurrent or metastatic GC patients, while chemotherapy treatment rather than red blood cell (RBC) transfusion can improve their prognosis. Additionally, platinum should not be recommended for treating severely anaemic GC patients.

Inhibiting effect of MicroRNA-3619-5p/PSMD10 axis on liver cancer cell growth in vivo and in vitro.

AIMS: Liver cancer is one of the leading causes of cancer death worldwide owing to its delayed diagnosis and absence of efficient treatment at advanced TNM stages. Increasing evidence demonstrated that microRNAs are implicated in tumorgenesis and cancer development by regulating cancer-related proteins. This study aimed to explore the effect of miR-3619-5p on cell growth in liver cancer. MAIN METHODS: The effect of miR-3619-5p on cell proliferation was measured by quantitative real-time PCR, MTT assay, flow cytometry, and Immunofluorescence assay. The interaction between miR-3619-5p and PSMD10 was validated using dual-luciferase. The expression of PSMD10 and Ki67 was further determined by immunohistochemistry. KEY FINDINGS: MiR-3619-5p over-expression remarkably inhibited cell proliferation and induced G1 phase arrest, accompanied with reduced expression of proliferating cell nuclear antigen. The expression of miR-3619-5p was negatively correlated to that of PSMD10, and PSMD10 was validated to be a downstream target of miR-3619-5p. Moreover, miR-3619-5p induced suppressed proliferation and G1 phase arrest were abrogated by elevated the expression of PSMD10 in liver cancer cells. PSMD10 over-expression also induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) and retinoblastoma protein (Rb1). Besides, elevated cyclin A, cyclin D1 and cyclin E expression supported that PSMD10 promoted the progress of cell cycle. In addition, miR-3619-5p inhibited tumor growth in vivo by targeting PSMD10, accompanied with blocked cell cycle. SIGNIFICANCE: In conclusion, our findings revealed that miR-3619-5p inhibits cancer cell proliferation by targeting PSMD10, and miR-3619-5p as a potential therapeutic target for the treatment of liver cancer.

Percutaneous occlusion of transseptal puncture-related free wall perforation at the coronary sinus with a ventricular septal occluder during left atrial appendage closure: A case report.

Coronary sinus perforation is a life-threatening complication of transseptal puncture and needs to be repaired immediately. In this study, we report a case of a 74-year-old female patient with nonvalvular atrial fibrillation, who is a poor long-term anticoagulation candidate. During the manipulation of transseptal puncture, a perforation of the free right atrial wall at the coronary sinus ostium occurred, which was caused by the Brockenbrough needle and followed by the immediate advancement of an 8.5-French transseptal sheath. In consideration of the danger of cardiac tamponade after sheath removal, we decided to leave the 8.5-French sheath in the pericardial cavity. Then, we advanced a 6 mm ventricular septal occluder through the sheath. Finally, we achieved successful deployment of the device and closure of the perforation under the guidance of fluoroscopy and transthoracic echocardiography. Subsequently, the left atrial appendage orifice was occluded with a 21 mm Watchman device. This case illustrates that percutaneous device closure is feasible for inadvertent perforation of the free right atrial wall at the coronary sinus during transseptal puncture and should be considered as an alternative to surgery.

Cardiac troponin I autoantibody induces myocardial dysfunction by PTEN signaling activation.

BACKGROUND: The objective of the current study was to study the molecular mechanism(s) underlying cardiac troponin I autoantibody (cTnIAAb) binding to cardiomyocyte and resultant myocardial damage/dysfunction. METHODS: cTnIAAb was purified from serum of 10 acute myocardial infarction (AMI) patients with left ventricular remodeling. Recombinant human cTnI was used to generate three mouse-derived monoclonal anti-cTnI antibodies (cTnImAb1, cTnImAb2, and cTnImAb3). The target proteins in cardiac myocyte membrane bound to cTnImAb and effect of cTnIAAb and cTnImAb on apoptosis and myocardial function were determined. FINDINGS: We found that cTnIAAb/cTnImAb1 directly bound to the cardiomyocyte membraneα-Enolase (ENO1) and triggered cell apoptosis via increased expression of ENO1 and Bax, decreased expression of Bcl2, subsequently activating Caspase8, Caspase 3, phosphatase and tensin homolog (PTEN) while inhibiting Akt activity. This cTnIAAb-ENO1-PTEN-Akt signaling axis contributed to increased myocardial apoptosis, myocardial collagen deposition, and impaired systolic dysfunction. INTERPRETATION: Results obtained in this study indicate that cTnIAAb is involved in the process of ventricular remodeling after myocardial injury. FUND: The National Natural Science Foundation of China (Grant#: 81260026).