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Background BRCA1 and BRCA2 (BRCA) mutation carriers face a high lifetime risk of developing ovarian cancer. Oral contraceptives are protective in this population; however, the impact of other types of contraception (e.g. intrauterine devices, implants, injections) is unknown. We undertook a matched case-control study to evaluate the relationship between type of contraception and risk of ovarian cancer among women with BRCA mutations. Methods A total of 1733 matched pairs were included in this analysis. Women were matched according to year of birth, date of study entry, country of residence, BRCA mutation type and history of breast cancer. Detailed information on hormonal, reproductive and lifestyle exposures were collected from a routinely administered questionnaire. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) associated with each contraceptive exposure. Results Ever use of any contraceptive was significantly associated with reduced risk of ovarian cancer (OR = 0.62; 95% CI 0.52–0.75; P < 0.0001), which was driven by significant inverse associations with oral contraceptives (OR = 0.66; 95% CI 0.54–0.79; P < 0.0001) and contraceptive implants (OR = 0.30; 95% CI 0.12–0.73; P = 0.008). We observed a similar effect with use of injections (OR = 0.37; 95% CI 0.10–1.38; P = 0.14), but this did not achieve significance. No significant associations were observed between patterns of intrauterine device use and risk of ovarian cancer. Conclusions These findings support a protective effect of oral contraceptives and implants on risk of ovarian cancer among women with BRCA mutations. The possible protective effect of injections requires further evaluation.

Background LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years. Methods LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 106 cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy. Results As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer. Conclusions The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM. Trial registration Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.

OBJECTIVE: To analyze the clinical characteristics of unilateral acoustic neuroma(AN) with normal hearing, so as to provide evidence for early identification AN. METHODS: Clinical datas from 73 patients of unilateral AN with normal hearing of Otorhinolaryngology Head and Neck Surgery of Beijing Tiantan Hospital affiliated of Capital Medical University from August 2019 to April 2022 admitted to department were retrospectively analyzed. All patients underwent pure tone audiometry(PTA), speech discrimination score(SDS), auditory brainstem response(ABR), distortion product otoacoustic emission(DPOAE) and head enhanced MRI. RESULTS: The incidence of normal hearing among patients with AN was 10.7%. Male∶female=1∶2.2; the mean age of the patients was(37.3±9.4) years; the mean tumor size was(24.2±11.2) mm. Tinnitus was the most common reason for visit; the patients who had headache and dizziness had larger tumors. Surgery was the main treatment, and the patients who underwent surgery had larger tumors than those of follow-up. Heterogeneous tumors were the most common type of MRI, homogeneous tumors were smaller than heterogeneous and cystic tumors. The sensitivity of ABR in the diagnosis of AN with normal hearing was 95.9%, and that of ≥20 mm tumors was 100%; prolonged Ⅴ-waves were the most common, patients with Ⅴ-wave deletion had larger tumors than those with normal or prolonged Ⅴ-waves. Patients who had the longer the Ⅴ-wave and the longer difference between Ⅰ-Ⅴ wave had larger tumors. DPOAE was not elicited at full frequency in 11 patients. There was no statistically significant difference in age among patients with different symptoms, treatments, types of MRI, ABR and DPOAE. CONCLUSION: AN of normal hearing was most common in 30-39 years old women. Patients had different symptoms, phenotypes of MRI and ABR. Patients with normal hearing who had tinnitus, dizziness, headache, facial paraesthesia, and recovery after sudden haring loss can be further examination of ABR and DPOAE for early identification AN. The sensitivity of ABR in diagnosis of hearing normal AN was 95.9%, and the abnormal type of Ⅴ-wave is related to tumor size.

Background The immunogenicity of the liver tumor microenvironment is clinically heterogeneous and mysterious. The insight into the role of immune cells including tumor-infiltrating lymphocytes (TILs) and chemokine networks, might enable optimal patient selection for immunotherapy. In this study, we aimed at characterizing the liver cancer immune subtypes linked to chemokines and associating with the patient characteristics and clinical outcomes. Methods We analyzed the immune cells and chemokine signatures of human liver cancer using The Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) database profiling of 110 normal liver tissues and 369 liver tumor patients. We performed hierarchical clustering to the chemokine expression by applying immune cells status to categorize the CCL5-related chemokine in liver tumors. The separation was characterized by dividing the liver tumor patients into CCL5-high and low subtypes. Results Our results showed that the high expression of myeloid-derived suppressor cells (MDSCs) is associated with a decrease in effector T cells expressing PRF1 in liver tumor progression. The chemokines and immune cells in CCL-5-high subtype including CCR5, MDSCs and effector T cells, are significantly associated with CCL5 and a potential predictive clinical benefit. The estimated odds for CCL5-low subtype liver tumors were higher than CCL5-high subtype liver tumors particularly in the stage IV tumors (OR = 3.54; 95 % CI: 0.36, 34.92). Our data demonstrated that the CCL5-high subtype significantly improved OS (p = 0.0379, hazard ratio 0.67; 95% CI 0.43, 0.98), DFI (p = 0.0104, hazard ratio 0.63; 95% CI 0.44, 0.90), PFI (p = 0.0066, hazard ratio 0.64; 95% CI 0.46, 0.89) and working performance status when compared to the CCL5-low subtype. Conclusion Our findings provide a novel perspective of liver cancer chemokine subtypes linked to immune cells. A suitable therapy that can effectively activate effector T cells and inhibit MDSCs targeting chemokines might support the magnitude of lymphocytic infiltration in liver tumors, and should be considered for the design of precision therapies targeting the tumor and its immune microenvironment. The chemokine signatures in the CCL5-subtype are a valuable resource for future research to help identify clinically relevant biomarkers.

Summary Polycomb group (PcG) proteins exist in distinct multi-protein complexes and play a central role in silencing developmental genes, yet the underlying mechanisms remain elusive. Here, we show that deficiency of retinoblastoma binding protein 4 (RBBP4), a component of the Polycomb repressive complex 2 (PRC2), in embryonic stem cells (ESCs) leads to spontaneous differentiation into mesendodermal lineages. We further show that Rbbp4 and core PRC2 share an important number of common genomic targets, encoding regulators involved in early germ layer specification. Moreover, we find that Rbbp4 is absolutely essential for genomic targeting of PRC2 to a subset of developmental genes. Interestingly, we demonstrate that Rbbp4 is necessary for sustaining the expression of Oct4 and Sox2 and that the forced co-expression of Oct4 and Sox2 fully rescues the pluripotency of Rbbp4-null ESCs. Therefore, our study indicates that Rbbp4 links maintenance of the pluripotency regulatory network with repression of mesendoderm lineages., Graphical Abstract, Highlights • RBBP4 deficiency in ESCs leads to spontaneous differentiation into mesendodermal lineages • Rbbp4 binding sites in ESCs substantially overlap with PRC2 binding • Rbbp4 is absolutely essential for PRC2 chromatin occupancy • Rbbp4 is necessary for sustaining the expression levels of Oct4 and Sox2, Polycomb group (PcG) proteins play a critical role in silencing developmental genes, yet the underlying mechanisms remain elusive. Yikai et al. report that PcG protein Rbbp4 represses developmental gene expression by recruiting PRC2 to the genes' promoter regions, thereby maintaining stem cell self-renewal and identity.

Colorectal cancer (CRC) is a common cancer with high metastatic property. Circular RNAs (circRNAs) have important involvement in cancer processes. This study focused on the regulation of circRNA RAD23 homologue B (circRAD23B) in CRC. The levels of circRAD23B, microRNA-1205 (miR-1205), and tripartite motif-44 (TRIM44) were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Functional analyses were performed by Cell Counting Kit-8 (CCK-8) for cell proliferation, flow cytometry for cell cycle or cell apoptosis, and transwell assay for cell migration and invasion. Western blot was administrated for protein detection. The interaction of targets was analyzed by dual-luciferase reporter and RNA pull-down assays. The in vivo experiment was conducted via xenograft tumor in mice. We identified that circRAD23B was overexpressed in CRC tissues and cells. CRC cell proliferation, cell cycle progression, and cell metastasis were inhibited, while apoptosis was promoted by downregulating circRAD23B. Target analysis indicated that circRAD23B-targeted miR-1205 and TRIM44 were downstream genes of miR-1205. Moreover, the antitumor response of circRAD23B downregulation and miR-1205 overexpression was, respectively, achieved by increasing miR-1205 and decreasing TRIM44. CircRAD23B could regulate TRIM44 level by sponging miR-1205. In vivo, circRAD23B knockdown also reduced CRC tumorigenesis via the miR-1205/TRIM44 axis. These results suggested that the inhibition of circRAD23B retarded the progression of CRC via acting on the miR-1205/TRIM44 axis. CircRAD23B might be a novel target in CRC treatment.

Background Human migration facilitate the spread of tuberculosis (TB). Migrants face an increased risk of TB infection. In this study, we aim to explore the spatial inequity of sputum smear-positive pulmonary TB (SS + PTB) in China; and the spatial heterogeneity between SS + PTB and internal migration. Methods Notified SS + PTB cases in 31 provinces in mainland China were obtained from the national web-based PTB surveillance system database. Internal migrant data were extracted from the report on China’s migrant population development. Spatial autocorrelations were explored using the global Moran’s statistic and local indicators of spatial association. The spatial variation in temporal trends was performed using Kulldorff’s scan statistic. Fixed effect and spatial autoregressive models were used to explore the spatial inequity between SS + PTB and internal migration. Results A total of 2 380 233 SS + PTB cases were reported in China between 2011 and 2017, of which, 1 716 382 (72.11%) were male and 663 851 (27.89%) were female. Over 70% of internal migrants were from rural households and had lower income and less education. The spatial variation in temporal trend results showed that there was an 9.9% average annual decrease in the notification rate of SS + PTB from 2011 to 2017; and spatial clustering of SS + PTB cases was mainly located in western and southern China. The spatial autocorrelation results revealed spatial clustering of internal migration each year (2011–2017), and the clusters were stable within most provinces. Internal emigration, urban-to-rural migration and GDP per capita were significantly associated with SS + PTB, further, internal emigration could explain more variation in SS + PTB in the eastern region in mainland. However, internal immigration and rural-to-urban migration were not significantly associated with SS + PTB across China. Conclusions Our study found the spatial inequity between SS + PTB and internal migration. Internal emigration, urban-to-rural migration and GDP per capita were statistically associated with SS + PTB; the negative association was identified between internal emigration, urban-to-rural migration and SS + PTB. Further, we found those migrants with lower income and less education, and most of them were from rural households. These findings can help stakeholders to implement effective PTB control strategies for areas at high risk of PTB and those with high rates of internal migration.

There are limited data on vascular, inflammatory, metabolic risk factors of dementia in Parkinson's disease (PD) with type 2 diabetes mellitus (DM) (PD-DM). In a study of 928 subjects comprising of 215 PD with DM (including 31 PD-DM with dementia, PD-DMD), 341 PD without DM (including 31 PD with dementia, PDD) and 372 DM without PD (including 35 DM with dementia, DMD) patients, we investigated if vascular, inflammatory, metabolic, and magnetic resonance imaging (MRI) markers were associated with dementia in PD-DM. Lower fasting blood glucose (FBG15μmol/L, OR=3.131; 95%CI: 1.243-7.888; p=0.015) and hyperlipidemia (OR=3.075; 95%CI: 1.142-8.277; p=0.026), increased age (OR=1.043; 95%CI: 1.003-1.084; p=0.034) were the most significant risk factors in PDD patients. Lower low-density lipoprotein cholesterol (LDL-C4g/L, OR=4.066; 95%CI: 1.467-11.274; p=0.007) were the most significant risk factors in PD-DMD patients. The area under the curve (AUC) for fibrinogen and LDL-C was 0.717 (P=0.001), with a sensitivity of 80.0% for the prediction of PD-DMD.In summary, we identified several factors including LDL-C and fibrinogen as significant risk factors for PD-DMD and these may have prognostic and treatment implications.

Follistatin (FS)-like 1 (FSTL1) is a member of the FS-SPARC (secreted protein, acidic and rich in cysteine) family of secreted and extracellular matrix proteins. The functions of FSTL1 have been studied in heart and lung injury as well as in wound healing; however, the role of FSTL1 in the kidney is largely unknown. Here, we show using single-cell RNA-Seq that Fstl1 was enriched in stromal cells in obstructed mouse kidneys. In addition, immunofluorescence demonstrated that FSTL1 expression was induced in fibroblasts during kidney fibrogenesis in mice and human patients. We demonstrate that FSTL1 overexpression increased renal fibrosis and activated the Wnt/β-catenin signaling pathway, known to promote kidney fibrosis, but not the transforming growth factor β (TGF-β), Notch, Hedgehog, or Yes-associated protein (YAP) signaling pathways in obstructed mouse kidneys, whereas inhibition of FSTL1 lowered Wnt/β-catenin signaling. Importantly, we show that FSTL1 interacted with Wnt ligands and the Frizzled (FZD) receptors but not the coreceptor lipoprotein receptor-related protein 6 (LRP6). Specifically, we found FSTL1 interacted with Wnt3a through its extracellular calcium-binding (EC) domain and von Willebrand factor type C-like (VWC) domain, and with FZD4 through its EC domain. Furthermore, we show that FSTL1 increased the association of Wnt3a with FZD4 and promoted Wnt/β-catenin signaling and fibrogenesis. The EC domain interacting with both Wnt3a and FZD4 also enhanced Wnt3a signaling. Therefore, we conclude that FSTL1 is a novel extracellular enhancer of the Wnt/β-catenin pathway.

Increasing evidences indicate that unlimited capacity for self-renewal and pluripotency, two unique properties of embryonic stem cells (ESCs), are intrinsically linked to cell cycle control. However, the precise mechanisms coordinating cell fate decisions and cell cycle regulation remain to be fully explored. Here, using CRISPR/Cas9-mediated genome editing, we show that in ESCs, deficiency of components of the cell cycle regulatory MuvB complex Lin54 or Lin52, but not Lin9 or Lin37, triggers G2/M arrest, loss of pluripotency, and spontaneous differentiation. Further dissection of these phenotypes demonstrated that this cell cycle arrest is accompanied by the gradual activation of mesoendodermal lineage-specifying genes. Strikingly, the abnormalities observed in Lin54-null ESCs were partially but significantly rescued by ectopic coexpression of genes encoding G2/M proteins Cyclin B1 and Cdk1. Thus, our study provides new insights into the mechanisms by which the MuvB complex determines cell fate through regulation of the cell cycle machinery.

Rationale: Vascular calcification in arterial intima is closely associated with atherosclerosis. Endothelial cells (ECs) sense blood flow and respond to the mechanical cues generated by different flow patterns. Laminar flow induces an anti-atherosclerotic EC phenotype whereas disturbed flow exerts an atheroprone effect. However, the contribution of blood flow to calcification in atherosclerotic arteries remains to be evaluated. Objective: We aim to investigate whether blood flow plays a determinant role in the distribution of vascular calcification and the underlying mechanisms involved. Methods and Results: Computed tomography angiography analysis of human coronary arteries (n=48) shows that calcification preferentially develops at flow perturbated sites. Similar phenomenon was observed in calcified human aortic valves and mouse arteries. Nonuniform shear stress produced in Y-shaped slide simulating live conditions in branched arteries promotes calcification in human umbilical vein ECs. The expression of KLF2 (Krüppel-like factor 2), a transcription factor inducible by laminar flow, is reduced in ECs of calcified human aortic valves and in endothelial calcification model, suggesting that KLF2 downregulation is likely involved in intimal calcification. Indeed, KLF2 silencing induces endothelial-to-mesenchymal transition and accelerates osteoinduction in both human aortic ECs and human umbilical vein ECs. EC-specific KLF2 knockdown promotes whereas AAV9 (adeno-associated virus serotype 9)-mediated EC-KLF2 overexpression ameliorates vascular calcification in ApoE −/− mice. Global mRNA profiling in human umbilical vein ECs reveals that KLF2 inhibits the BMP (bone morphogenetic proteins)/SMAD1/5 pathway which is critical in vascular calcification. Furthermore, KLF2 mediates laminar flow-induced inhibition of the BMP/SMAD1/5 pathway. By contrast, disturbed flow-induced activation of BMP/SMAD1/5 pathway is suppressed by KLF2 overexpression. Mechanistically, KLF2 binds to the promoters of BMP4 , BMPER , and SMAD1 to directly regulate their expression in ECs. Conclusions: Vascular calcification prefers to occur at branched or bifurcated areas of vasculature. Laminar flow inhibits vascular calcification through KLF2-mediated inhibition of endothelial BMP/SMAD1/5 signaling. Targeting KLF2 may represent a novel therapeutic approach against vascular calcification.

Chimeric antigen receptor T (CAR-T) cell therapy is a novel cellular immunotherapy that is widely used to treat hematological malignancies, including acute leukemia, lymphoma, and multiple myeloma. Despite its remarkable clinical effects, this therapy has side effects that cannot be underestimated. Cytokine release syndrome (CRS) is one of the most clinically important and potentially life-threatening toxicities. This syndrome is a systemic immune storm that involves the mass cytokines releasing by activated immune cells. This phenomenon causes multisystem damages and sometimes even death. In this study, we reported the management of a patient with recurrent and refractory multiple myeloma and three patients with acute lymphocytic leukemia who suffered CRS during CAR-T treatment. The early application of tocilizumab, an anti-IL-6 receptor antibody, according to toxicity grading and clinical manifestation is recommended especially for patients who suffer continuous hyperpyrexia, hypotensive shock, acute respiratory failure, and whose CRS toxicities deteriorated rapidly. Moreover, low doses of dexamethasone (5-10 mg/day) were used for refractory CRS not responding to tocilizumab. The effective management of the toxicities associated with CRS will bring additional survival opportunities and improve the quality of life for patients with cancer.

Triptolide is a major active ingredient isolated from the traditional Chinese herb Tripterygium wilfordii Hook F. However, its use in clinical practice is limited due to its severe hepatotoxicity. Autophagy, a highly conserved intracellular process, is essential for maintaining cytoplasmic homeostasis. Considering that abnormalities in autophagy are closely associated with drug-mediated hepatotoxicity, we applied human normal liver HL7702 cells to elucidate the roles of autophagy in triptolide-induced hepatotoxicity. Our study revealed that triptolide was cytotoxic to HL7702 cells. It markedly increased autophagosome formation and expression of autophagy-related proteins, namely Beclin1 and microtubule-associated protein 1 light chain 3II, and induced oxidative stress. These proautophagic effects were counteracted by pretreatment with N-acetylcysteine, a reactive oxygen species scavenger. Moreover, the pharmacological suppression of autophagy further exacerbated triptolide-elicited decrease in cell viability, increase in lactate dehydrogenase leakage, and activation of apoptosis proteases (caspase 3 and caspase 9). Our findings suggest that triptolide-induced oxidative stress consequently enhances autophagic activity, and autophagy is a cytoprotective mechanism against triptolide-induced cytotoxicity in HL7702 cells.

Understanding the mechanisms of malignancy in acute myeloid leukemia (AML) cell is important for the targeted treatment and drug development. We found that visfatin, a 52-kDa adipokine, can positively regulate the proliferation of AML cells. Targeted inhibition of visfatin via its specific siRNAs or inhibitor can suppress the proliferation of AML cells. Further, knockdown of visfatin can increase the doxorubicin (Dox) and cisplatin (CDDP) sensitivity of AML cells. Among the tested six cytokines, si-visfatin can decrease the expression of interleukin-17 (IL-17). Over expression of IL-17 can reverse si-visfatin suppressed cell proliferation and increased Dox sensitivity. The upregulation of IL-17 was also involved in visfatin induced activation of PI3K/Akt signals in AML cells. The inhibitor of PI3K/Akt can synergistically suppress the proliferation of HL60 cells which were transfected with si-visfatin. Knockdown of visfatin can increase the expression of miR-135a, which can bind to the 3'UTR of IL-17 and decrease its expression. The inhibitor of miR-135a can attenuate si-visfatin suppressed expression of IL-17 and proliferation of AML cells. Collectively, our data suggested that visfatin can increase the malignancy of AML cells via regulation of miR-135a/IL-17/PI3K/Akt signals.

ObjectivesTo investigate the expression levels of aromatase cytochrome P450 enzyme (P450AROM) and related molecules—estrogen receptor-beta (ER-β), Ki-67, and p53—in prolactinoma tumor tissue from pre- and post-menopausal women, and to determine the associations of tumor invasiveness with expression levels of these genes.MethodsThis study recruited 90 patients with prolactinoma who underwent adenoidectomy between 2012 and 2017. Information was collected regarding clinical characteristics, hormones, laboratory tests, and magnetic resonance imaging-assessed tumor invasiveness. Expression levels of P450AROM, ER-β, Ki-67, and p53 were examined by immunohistochemistry in prolactinoma tissues.ResultsIncreased P450AROM expression was found in invasive prolactinoma tissues in post-menopausal women, compared with its expression in non-invasive prolactinoma tissues. ER-β level was significantly higher in patients resistant to treatment with bromocriptine, a dopamine agonist. However, there were no differences in rate of resistance to treatment (8.2% vs. 3.4%) or expression levels of P450AROM, Ki-67, p53, and ER-β between pre- and post-menopausal patients.ConclusionsOur results demonstrated that increased P450AROM expression in prolactinoma of post-menopausal women was positively associated with invasiveness. Moreover, ER-β level was higher in both pre- and post-menopausal patients who were resistant to dopamine agonist treatment.

ContextLH receptor (LHR) expression has been shown to be regulated posttranscriptionally by LHR mRNA binding protein (LRBP) in rodent and human ovaries. LRBP was characterized as mevalonate kinase. The gene that encodes mevalonate kinase is a member of a family of genes that encode enzymes involved in lipid synthesis and are regulated by the transcription factor sterol regulatory element binding proteins (SREBPs).ObjectiveThe current study examined the regulation of LHR mRNA expression in human granulosa-lutein cells in response to alterations in cholesterol metabolism.DesignUsing atorvastatin, an inhibitor of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase to inhibit cholesterol biosynthesis, we examined its effect on LHR mRNA expression. The effect of atorvastatin on SREBP and mRNA expression as well as LHR mRNA binding protein expression was examined. Finally, the effect of atorvastatin on human chorionic gonadotropin (hCG)–stimulated progesterone production and the expression of key steroidogenic enzymes was also examined.ResultsStatin treatment reduced LHR mRNA expression by increasing the levels of SREBP1a and SREBP2, leading to an increase in LRBP. RNA gel shift assay showed that increased binding of LHR mRNA to LRBP occurred in response to atorvastatin, leading to LHR mRNA degradation. The granulosa-lutein cells pretreated with atorvastatin also showed decreased responsiveness to hCG by decreasing the mRNA and protein expression of steroidogenic enzymes. Atorvastatin also attenuated LH/hCG-induced progesterone production.ConclusionThese results imply that LHR mRNA expression by the human granulosa-lutein cells is regulated by cholesterol, through a mechanism involving SREBP and SREBP cleavage activating protein serving as the cholesterol sensor.

Background Chimeric antigen receptor (CAR) T cell therapy has demonstrated proven efficacy in some hematologic cancers. We evaluated the safety and efficacy of LCAR-B38M, a dual epitope-binding CAR T cell therapy directed against 2 distinct B cell maturation antigen epitopes, in patients with relapsed/refractory (R/R) multiple myeloma (MM). Methods This ongoing phase 1, single-arm, open-label, multicenter study enrolled patients (18 to 80 years) with R/R MM. Lymphodepletion was performed using cyclophosphamide 300 mg/m2. LCAR-B38M CAR T cells (median CAR+ T cells, 0.5 × 106 cells/kg [range, 0.07 to 2.1 × 106]) were infused in 3 separate infusions. The primary objective is to evaluate the safety of LCAR-B38M CAR T cells; the secondary objective is to evaluate the antimyeloma response of the treatment based on the general guidelines of the International Myeloma Working Group. Results At data cutoff, 57 patients had received LCAR-B38M CAR T cells. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were reported in 37/57 patients (65%); most common were leukopenia (17/57; 30%), thrombocytopenia (13/57; 23%), and aspartate aminotransferase increased (12/57; 21%). Cytokine release syndrome occurred in 51/57 patients (90%); 4/57 (7%) had grade ≥ 3 cases. One patient reported neurotoxicity of grade 1 aphasia, agitation, and seizure-like activity. The overall response rate was 88% (95% confidence interval [CI], 76 to 95); 39/57 patients (68%) achieved a complete response, 3/57 (5%) achieved a very good partial response, and 8/57 (14%) achieved a partial response. Minimal residual disease was negative for 36/57 (63%) patients. The median time to response was 1 month (range, 0.4 to 3.5). At a median follow-up of 8 months, median progression-free survival was 15 months (95% CI, 11 to not estimable). Median overall survival for all patients was not reached. Conclusions LCAR-B38M CAR T cell therapy displayed a manageable safety profile and demonstrated deep and durable responses in patients with R/R MM. Trial registration ClinicalTrials.gov, NCT03090659; Registered on March 27, 2017, retrospectively registered Electronic supplementary material The online version of this article (10.1186/s13045-018-0681-6) contains supplementary material, which is available to authorized users.

Introduction and objective To improve the complete remission (CR) rate of newly diagnosed acute myeloid leukemia (AML) patients and alleviate the severe side effects of double induction chemotherapy, we combined a standard regimen with granulocyte colony-stimulating factor (G-CSF) priming chemotherapy to compose a new double induction regimen for AML patients who failed to achieve CR after the first course. Patients and methods Ninety-seven patients with AML who did not achieve CR after the first course of standard chemotherapy were enrolled. Among them, 45 patients received G-CSF priming combined with low-dose chemotherapy during days 20–22 of the first course of chemotherapy, serving as priming group, 52 patients were administered standard chemotherapy again, serving as control group. Results Between the two groups there were no differences in the French–American–British (FAB) classification, risk status, the first course of chemotherapy, blood cell count or blasts percentage of bone marrow before the second course. But the CR rate was significantly higher and the adverse effect was much lower in the priming group than the control group. Cox multivariate regression analysis showed that WBC level before the second course and the selection of the second chemotherapy regimen were two independent factors for long survival of patients. Discussion These results elucidate that standard chemotherapy followed by G-CSF priming new double induction chemotherapy is an effective method for AML patients to improve CR rate and reduce adverse effects.

Background Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance in pregnancy and without a history of diabetes mellitus. While there are limited metabolomic studies involving advanced maternal age in China, we aim to investigate the metabolomic profiling of plasma and urine in pregnancies complicated with GDM aged at 35–40 years at early and late gestation. Methods Twenty normal and 20 GDM pregnant participants (≥ 35 years old) were enlisted from the Complex Lipids in Mothers and Babies (CLIMB) study. Maternal plasma and urine collected at the first and third trimester were detected using gas chromatography-mass spectrometry (GC-MS). Results One hundred sixty-five metabolites and 192 metabolites were found in plasma and urine respectively. Urine metabolomic profiles were incapable to distinguish GDM from controls, in comparison, there were 14 and 39 significantly different plasma metabolites between the two groups in first and third trimester respectively. Especially, by integrating seven metabolites including cysteine, malonic acid, alanine, 11,14-eicosadienoic acid, stearic acid, arachidic acid, and 2-methyloctadecanoic acid using multivariant receiver operating characteristic models, we were capable of discriminating GDM from normal pregnancies with an area under curve of 0.928 at first trimester. Conclusion This study explores metabolomic profiles between GDM and normal pregnancies at the age of 35–40 years longitudinally. Several compounds have the potential to be biomarkers to predict GDM with advanced maternal age. Moreover, the discordant metabolome profiles between the two groups could be useful to understand the etiology of GDM with advanced maternal age.

The immune system has been increasingly recognized as a major contributor in the pathogenesis of Parkinson’s disease (PD). The double-edged nature of the immune system poses a problem in harnessing immunomodulatory therapies to prevent and slow the progression of this debilitating disease. To tackle this conundrum, understanding the mechanisms underlying immune-mediated neuronal death will aid in the identification of neuroprotective strategies to preserve dopaminergic neurons. Specific innate and adaptive immune mediators may directly or indirectly induce dopaminergic neuronal death. Genetic factors, the gut-brain axis and the recent identification of PD-specific T cells may provide novel mechanistic insights on PD pathogenesis. Future studies to address the gaps in the identification of autoantibodies, variability in immunophenotyping studies and the contribution of gut dysbiosis to PD may eventually provide new therapeutic targets for PD.

Objective We aimed to identify key susceptibility gene targets in multiple datasets generated from postmortem brains and blood of Parkinson’s disease (PD) patients and healthy controls (HC). Methods We performed a multitiered analysis to integrate the gene expression data using multiple-gene chips from 244 human postmortem tissues. We identified hub node genes in the highly PD-related consensus module by constructing protein–protein interaction (PPI) networks. Next, we validated the top four interacting genes in 238 subjects (90 sporadic PD, 125 HC and 23 Parkinson’s Plus Syndrome (PPS)). Utilizing multinomial logistic regression analysis (MLRA) and receiver operating characteristic (ROC), we analyzed the risk factors and diagnostic power for discriminating PD from HC and PPS. Results We identified 1333 genes that were significantly different between PD and HCs based on seven microarray datasets. The identified MEturquoise module is related to synaptic vesicle trafficking (SVT) dysfunction in PD (P Conclusions This study highlights that SVT genes, especially SYNJ1, may be promising markers in discriminating PD from HCs and PPS.

BACKGROUND Mild parkinsonian signs (MPS) are common in the older adult and associated with a wide range of adverse health outcomes. There is limited data on the prevalence of MPS and its significance. OBJECTIVE To determine the prevalence of MPS in the community ambulant population and to evaluate the relationship of MPS with prodromal features of Parkinson's disease (PD) and cognition. METHODS This cross-sectional community-based study involved participants aged ≥50 years. Parkinsonian signs were assessed using the modified Unified Parkinson's Disease Rating Scale (mUPDRS) and cognition using the Montreal Cognitive Assessment (MoCA). Premotor symptoms of PD were screened using a self-reported questionnaire. Linear regression was used to assess the association of MPS with premotor symptoms of PD and cognitive impairment. RESULTS Of 392 eligible participants, MPS was present in 105 (26.8%). Mean age of participants with MPS was 68.8±6.9 years and without MPS was 66.1±5.9 years (p

Background The serine/threonine kinases MST1 and MST2 are core components of the Hippo pathway, which has been found to be critically involved in embryonic kidney development. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the pathway's main effectors. However, the biologic functions of the Hippo/YAP pathway in adult kidneys are not well understood, and the functional role of MST1 and MST2 in the kidney has not been studied. Methods We used immunohistochemistry to examine expression in mouse kidneys of MST1 and MST2, homologs of Hippo in Drosophila. We generated mice with tubule-specific double knockout of Mst1 and Mst2 or triple knockout of Mst1, Mst2, and Yap. PCR array and mouse inner medullary collecting duct cells were used to identify the primary target of Mst1/Mst2 deficiency. Results MST1 and MST2 were predominantly expressed in the tubular epithelial cells of adult kidneys. Deletion of Mst1/Mst2 in renal tubules increased activity of YAP but not TAZ. The kidneys of mutant mice showed progressive inflammation, tubular and glomerular damage, fibrosis, and functional impairment; these phenotypes were largely rescued by deletion of Yap in renal tubules. TNF-α expression was induced via both YAP-dependent and YAP-independent mechanisms, and TNF-α and YAP amplified the signaling activities of each other in the tubules of kidneys with double knockout of Mst1/Mst2. Conclusions Our findings show that tubular Mst1/Mst2 deficiency leads to CKD through both the YAP and non-YAP pathways and that tubular YAP activation induces renal fibrosis. The pathogenesis seems to involve the reciprocal stimulation of TNF-α and YAP signaling activities.

Multiple lines of evidence indicate that immune system dysfunction has a role in Parkinson disease (PD); this evidence includes clinical and genetic associations between autoimmune disease and PD, impaired cellular and humoral immune responses in PD, imaging evidence of inflammatory cell activation and evidence of immune dysregulation in experimental models of PD. However, the mechanisms that link the immune system with PD remain unclear, and the temporal relationships of innate and adaptive immune responses with neurodegeneration are unknown. Despite these challenges, our current knowledge provides opportunities to develop immune-targeted therapeutic strategies for testing in PD, and clinical studies of some approaches are under way. In this Review, we provide an overview of the clinical observations, preclinical experiments and clinical studies that provide evidence for involvement of the immune system in PD and that help to define the nature of this association. We consider autoimmune mechanisms, central and peripheral inflammatory mechanisms and immunogenetic factors. We also discuss the use of this knowledge to develop immune-based therapeutic approaches, including immunotherapy that targets α-synuclein and the targeting of immune mediators such as inflammasomes. We also consider future research and clinical trials necessary to maximize the potential of targeting the immune system.

How diet is related with cognition and health has not been systematically examined in Asians whose eating habits are very different from their counterparts in the West and the biological mechanisms underlying such links are not well known yet. The diet and healthy aging (DaHA) study is a community-based longitudinal study conducted to examine the role of diet and nutrition in promoting cognitive, emotional, and physical health among community-living elderly Singaporeans. The first wave of DaHA, conducted from 2011 to 2017, provided detailed information on diet and baseline cognitive function and health from 1010 community-living elderly in Singapore. Biomarkers of oxidative stress, systemic inflammation, and genetic information were collected. The ongoing second wave of DaHA is conducted from 2017 to 2020, which provides follow- up assessments using established cognitive tests and clinical tools. This well-characterized cohort, with its archived biological samples and high-quality data on diet and lifestyle factors will allow researchers to explore the relationships among diet, nutrition, genes, cognition, mental and physical health in an extremely cost-effective manner. Translations of the research findings into clinical and public health practices will potentially help to promote cognitive health at the population level and reduce healthcare costs related to cognitive impairment. National Medical Research Council (NMRC) Published version This work is supported by the following grants awarded to Dr Lei Feng: the National University of Singapore Virtual Institute for the Study of Ageing [grant number VG-8]; the Alice Lim Memorial Fund, Singapore [grant number ALMFA/2010]; the National Medical Research Council of Singapore [grant number NMRC/TA/ 0053/2016].

The K+-Cl- co-transporter 2 (KCC2) is a neuron-specific Cl- extruder in the dorsal horn of spinal cord. The low intracellular Cl- concentration established by KCC2 is critical for GABAergic and glycinergic systems to generate synaptic inhibition. Peripheral nerve lesions have been shown to cause KCC2 dysfunction in adult spinal cord through brain-derived neurotrophic factor (BDNF) signaling, which switches the hyperpolarizing inhibitory transmission to be depolarizing and excitatory. However, the mechanisms by which BDNF impairs KCC2 function remain to be elucidated. Here we found that BDNF treatment enhanced KCC2 ubiquitination in the dorsal horn of adult mice, a post-translational modification that leads to KCC2 degradation. Our data showed that spinal BDNF application promoted KCC2 interaction with Casitas B-lineage lymphoma b (Cbl-b), one of the E3 ubiquitin ligases that are involved in the spinal processing of nociceptive information. Knockdown of Cbl-b expression decreased KCC2 ubiquitination level and attenuated the pain hypersensitivity induced by BDNF. Spared nerve injury significantly increased KCC2 ubiquitination, which could be reversed by inhibition of TrkB receptor. Our data implicated that KCC2 was one of the important pain-related substrates of Cbl-b and that ubiquitin modification contributed to BDNF-induced KCC2 hypofunction in the spinal cord.

While tuberculosis (TB) in pregnant women is reported globally, clinical data is unavailable in China. To describe clinical features and identify difficulties in the diagnosis of pregnancy-related TB, we performed a retrospective study of 28 TB inpatients at Beijing Chest Hospital. The results were presented in terms of interquartile range (IQR) for age, and medians and percentages with respect to the categorical variables. One patient (3.6%) was immediately diagnosed; for 27 patients (96.4%), the median interval from the initial onset of symptoms to diagnosis was five weeks. Eight cases (28.6%) were microbiologically confirmed. 22 (78.6%) were pulmonary TB (PTB), while six (21.4%) were extrapulmonary TB (EPTB). In addition, eight (28.6%) were miliary TB and six (21.4%) were cerebral TB. 27 (96.4%) were cured and one (3.6%) died. 15 neonates were identified, nine of which were healthy. Two were small for the gestational age (SGA) and one was a stillbirth. Three had neonatal TB, one of which died. Nine were legal abortions and four were spontaneous abortions. Indeed, there was a substantial delay in the diagnosis of TB in the pregnant women and a high incidence of both miliary and cerebral TB was evident. With timely treatment, prognosis is positive.

To investigate the transcriptional regulation of transcription factor MZF-1 on acute monocytic leukemia-related gene MLAA-34.The effect of MZF-1 on the transcriptional activity of MLAA-34 gene promoter was analyzed by luciferase reporter gene detection system and site-directed mutation technique. The EMSA and ChIP assay were used to verify whether MZF-1 directly and specifically binds to the core region of MLAA-34 promoter. The over-expression vector and interference vector of MZF-1 were constructed to transfect U937 cells, and RT-PCR and Western blot were used to detect the transcription and expression changes of MLAA-34 gene.The transcription factor MZF-1 had a regulatory effect on MLAA-34 gene expression, and the relative luciferase activity was decreased after MZF-1 binding point mutation (P0.01). EMSA and ChIP experiments demonstrated that MZF-1 could directly bind to MLAA-34 promoter and play a regulatory role. In the over-expression test, the increase of MZF-1 could up-regulate the expression of MLAA-34 (P0.05). In the interference test, the decrease of MZF-1 could down-regulate the expression of MLAA-34 (P0.05).Transcription factor MZF-1 can bind to the transcriptional regulatory region on the promoter of MLAA-34 gene and promote the transcription of MLAA-34 gene in acute monocytic leukemia.转录因子MZF-1对急性单核细胞白血病新抗原基因MLAA-34的转录调控研究.探讨转录因子MZF-1对急性单核细胞白血病新抗原基因MLAA-34的转录调控作用.利用双萤光素酶报告基因检测系统及定点突变技术分析MZF-1 对MLAA-34基因启动子转录活性的影响。通过凝胶电泳迁移率变动检测（electrophoretic mobility slift assay,EMSA）和染色质免疫沉淀检测（chromatin immunoprecipitation,ChIP）实验，验证MZF-1是否与MLAA-34启动子核心区直接特异性结合。构建MZF-1真核表达载体和干涉载体，转染U937细胞，应用RT-PCR 和Western blot法检测MLAA-34基因的转录和表达变化.转录因子MZF-1对MLAA-34基因表达具有调控作用，MZF-1结合序列点突变后，相对荧光素酶活性降低（P0.01）。EMSA和ChIP实验从细胞内、外水平分别证明MZF-1可与MLAA-34启动子直接结合而发挥调控作用。在过表达试验中，MZF-1的增加可上调MLAA-34的表达（P0.05）；在干涉试验中，MZF-1的降低可下调MLAA-34的表达（P0.05）.转录因子MZF-1可与MLAA-34基因启动子上的转录调控区结合，并促进急性单核细胞白血病细胞中MLAA-34基因的转录.

Inferring brain connectivity network and quantifying the significance of interactions between brain regions are of paramount importance in neuroscience. Although there have recently emerged some tests for graph inference based on independent samples, there is no readily available solution to test the change of brain network for paired and correlated samples. In this article, we develop a paired test of matrix graphs to infer brain connectivity network when the groups of samples are correlated. The proposed test statistic is both bias corrected and variance corrected, and achieves a small estimation error rate. The subsequent multiple testing procedure built on this test statistic is guaranteed to asymptotically control the false discovery rate at the pre-specified level. Both the methodology and theory of the new test are considerably different from the two independent samples framework, owing to the strong correlations of measurements on the same subjects before and after the stimulus activity. We illustrate the efficacy of our proposal through simulations and an analysis of an Alzheimer's Disease Neuroimaing Initiative dataset., 30 pages, 1 figure, 5 tables

To clone the promoter sequence of acute monocytic leukemia new antigen gene.MLAA-34 and identify its promoter core region.The full-length fragment of MLAA-34 gene promoter region was amplified by PCR, then was ligated into pGL3-Basic vector, and the recombinant plasmid was cloned. Constructed a series of MLAA-34 gene promoter 5' flanking region truncated plasmid. These recombinant plasmids were transfected into U937 and HEK293 cells, and the dual luciferase reporter gene was used to detect the promoter activity of each fragment to determine the minimum active region. Transcription factor binding sites were analyzed by bioinformatics methods.The recombinant plasmid containing MLAA-34 promoter sequence and its truncated plasmid were successfully constructed, and the promoter activity was significantly increased as compared with the empty vector (P＜0.001). The minimal active region of MLAA-34 located between 402 bp and 200 bp. It contained multiple transcription factor binding sites such as E2F1, MZF-1, SP1, USF2 and STAT3.The promoter of luciferase reporter gene has been successfully constructed with different deletion fragments of MLAA-34, and its core promoter region may contain multiple transcription factor sequence.急性单核细胞白血病新抗原基因MLAA-34启动子的克隆及其核心区鉴定.克隆急性单核细胞白血病新抗原基因MLAA-34上游启动子序列并检测其活性、鉴定核心区域.PCR扩增 MLAA-34基因启动子区全长片段,将其连接至pGL3Basic 载体，克隆重组质粒; 构建一系列 MLAA-34基因启动子 5′侧翼区截短质粒; 将含MLAA-34启动子序列的重组质粒及其截短型质粒转染至U937、HEK293细胞，应用双荧光素酶报告基因检测各片段的启动子活性，确定启动子最小活性区域，并通过生物信息学方法分析转录因子结合位点.构建了含有MLAA-34启动子序列的重组质粒及其截短型质粒；与空载体相比，其启动子活性明显增加(P＜0.001) MLAA-34最小活性区域位于转录起始位点－402 bp至－200 bp之间，其中包含E2F1，MZF-1，SP1，USF2和STAT3等多个转录因子结合位点.成功构建急性单核细胞白血病新抗原基因MLAA-34不同缺失片段的启动子荧光素酶报告基因重组质粒，鉴定出核心启动子区，其中含有多个潜在的转录因子结合序列.

The present study aimed to construct conditionally replicative adenovirus (CRAds) carrying small hairpin (sh)RNA targeting enhancer of zeste homolog 2 (EZH2), in order to study its effect on inhibiting prostate cancer (PCa) cell growth and invasion. Immunohistochemical analyses of EZH2 was performed in tumor tissue samples from PCa and benign prostate hyperplasia (BPH). The human telomerase reverse transcriptase (hTERT) promoter was chosen to transcriptionally control EZH2 gene expression to obtain adenoviral replication (Ad‑hTERT‑EZH2shRNA) in human PCa cell lines. The inhibitory effect of Ad‑hTERT‑EZH2shRNA on EZH2 expression was evaluated by reverse transcription‑-quantitative polymerase chain reaction and western blot analyses. Cell Counting Kit‑8 assays were used to examine the effects of the Ad‑hTERT‑EZH2shRNA on cell proliferation. Transwell Matrigel invasion assays were used to detected cell invasion. Immunohistochemistry showed that EZH2 staining was stronger in castration‑resistant prostate cancer (CRPC) samples, compared with androgen‑dependent prostate cancer (ADPC) samples, and was absent in BPH. Furthermore, EZH2 expression knockdown suppressed PCa cell proliferation and invasion. In addition, it was found that Ad‑hTERT‑EZH2shRNA selectively replicated and significantly reduced the expression of EZH2 in PCa cells lines. The growth ability and invasion of DU145 and PC3 cells in vitro was effectively inhibited by Ad‑hTERT‑EZH2shRNA. Silencing the expression of EZH2 led to decreased expression of CCND1 and Ki67 and increased expression of E‑cadherin, as determined by western blot analysis. Thus, it was shown that CRAds armed with EZH2 shRNA exhibited significant antitumor effects in human PCa cells. Ad‑hTERT‑EZH2shRNA may be developed as a treatment for hormone‑refractory PCa.

BACKGROUND Klotho G-395-A gene polymorphism is associated with several diseases; however, its association with calcium-phosphate metabolism disorders in end-stage renal disease (ESRD) is unknown. METHODS A total of 137 patients with ESRD and 80 healthy adults (control) were enrolled in the study. Patients with ESRD were divided into three subgroups: haemodialysis (A1, n = 52), peritoneal dialysis (A2, n = 30), and non-dialysis (A3, n = 55). The klotho G-395-A genotype was detected by TaqMan PCR assay, and ELISA was used to detect the soluble klotho protein (sKL) and fibroblast growth factor (FGF23). Intact parathyroid hormone (iPTH) and other related clinical biochemical parameters were also analyzed for all subjects. RESULTS (i) Three genotypes (GG, GA and AA) of KL G-395A were detected, and a significant difference between the ESRD and control groups was observed, (ii) sKL was inversely associated with FGF23 in each subgroup and phosphate and positively associated with calcium in A1 and A3. FGF23 was positively associated with phosphate and inversely associated with calcium in each subgroup, (iii) a statistical difference in levels of sKL and FGF23 was observed between GG and AA, as well as between GA and AA. The expression of sKL was lowest and the level of FGF23 was highest in AA and (iv). GA + AA genotypes and FGF23 were risk factors and sKL might be protective factor of calcium-phosphate metabolism disorders. CONCLUSION Soluble klotho protein and FGF23 were associated with the regulation of calcium and phosphate metabolism, and the A allele of the G-395A klotho gene polymorphism could be a risk factor on calcium-phosphate metabolism disorders in patients with ESRD.

// Ying Shi 1, * , Xiao-Xiao Huang 1, * , Guo-Bin Chen 1, 6, * , Ying Wang 1 , Qiang Zhi 1 , Yuan-Sheng Liu 1 , Xiao-Ling Wu 1 , Li-Fen Wang 1 , Bing Yang 1 , Chuan-Xing Xiao 1 , Hui-Qin Xing 5 , Jian-Lin Ren 1 , Yin Xia 3, 4 , Bayasi Guleng 1, 2 1 Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, China 2 State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, China 3 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China 4 School of Biomedical Sciences Core Laboratory, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, China 5 Department of Basic Medical Sciences, Institute of Neuroscience, Medical College of Xiamen University, Xiamen, China 6 Xiamen Branch, Zhongshan Hospital, Fudan University, Xiamen, China * These authors contributed equally to this work Correspondence to: Bayasi Guleng, email: bayasi@xmu.edu.cn Yin Xia, email: Xia.Yin@cuhk.edu.hk Ying Shi, email: shiying@stu.xmu.edu.cn Keywords: Dragon, oxaliplatin resistance, colon cancer, JNK, p38 MAPK Received: December 21, 2015 Accepted: June 12, 2016 Published: June 30, 2016 ABSTRACT Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality. Chemotherapy resistance remains a major challenge for treating advanced CRC. Therefore, the identification of targets that induce drug resistance is a priority for the development of novel agents to overcome resistance. Dragon (also known as RGMb) is a member of the repulsive guidance molecule (RGM) family. We previously showed that Dragon expression increases with CRC progression in human patients. In the present study, we found that Dragon inhibited apoptosis and increased viability of CMT93 and HCT116 cells in the presence of oxaliplatin. Dragon induced resistance of xenograft tumor to oxaliplatinin treatment in mice. Mechanistically, Dragon inhibited oxaliplatin-induced JNK and p38 MAPK activation, and caspase-3 and PARP cleavages. Our results indicate that Dragon may be a novel target that induces drug resistance in CRC.

Background Patients 8 courses of chemotherapy (high-dose CHOP, CHOP-E, EPOCH, MAED, MMED, and HyperCVAD). The control group included 91 patients (46.0%) who received 6–8 courses of CHOP-based treatment. Response rate (RR), survival, relapse, and adverse effects were compared. Results Baseline characteristics of the patients were similar between the 2 groups. Median follow-up was 64.5 months. RR in the high-intensity and control groups was 88.8% and 84.6% (P=0.387), respectively; 5-year overall survival was 66.4% and 36.3% (P

Image-based tracking for motion compensation is an important topic in image-guided interventions, as it enables physicians to operate in a less complex space. In this paper, we propose an automatic motion compensation scheme to boost image guidence power in transcatheter aortic valve implantation (TAVI). The proposed tracking algorithm automatically discovers reliable regions that correlate strongly with the target. These discovered regions can assist to estimate target motion under severe occlusion, even if target tracker fails. We evaluate the proposed method for pigtail tracking during TAVI. We obtain significant improvement (12 %) over the baseline in a clinical dataset. Calcification regions are automatically discovered during tracking, which would aid TAVI processes. In this work, we open a new paradigm to provide dynamic real-time guidance for TAVI without user interventions, specially in case of severe occlusion where conventional tracking methods are challenged.

Background Extranodal NK/T-cell lymphoma (ENKTL) of the nasal type is highly invasive and relatively resistant to chemotherapy. This study aimed to assess the efficacy and safety of an extended chemotherapy regimen with increased dose intensity. Material/Methods This was a retrospective cohort study of 69 patients 8 courses of high-intensity chemotherapy (n=37) vs. 6–8 courses (n=18) and 8 courses group. Results The mean follow-up was 52 months (8 to 82 months). Remission rate did not differ significantly when compared among the 3 groups after 3 courses of chemotherapy (83.8%, 77.8%, and 78.6%, respectively, overall P=0.834), but the 5-year overall survival (OS) differed significantly (63.5%, 45.1%, and 22.9%, respectively, overall P=0.030), as did progression-free survival (PFS) (59.1%, 36.0%, and 15.1%, respectively, overall P=0.020), disease-free survival (DFS) (54.1%, 35.5%, and 12.9%, respectively, overall P=0.022), and total relapse rate throughout follow-up (37.04%, 50.0%, and 88.89%, respectively, overall P=0.027). There were no differences in adverse effects among the 3 groups. Conclusions These results suggest improved OS, PFS, DFS, and relapse rate in young patients with ENKTL receiving >8 courses of high-intensity chemotherapy.

Parkinson’s disease (PD) is the most common movement disorder with motor and nonmotor signs. The current therapeutic regimen for PD is mainly symptomatic as the etio-pathophysiology has not been fully elucidated. A variety of animal models has been generated to study different aspects of the disease for understanding the pathogenesis and therapeutic development. The disease model can be generated through neurotoxin-based or genetic-based approaches in a wide range of animals such as non-human primates (NHP), rodents, zebrafish, Caenorhabditis (C.) elegans, and drosophila. Cellular-based disease model is frequently used because of the ease of manipulation and suitability for large-screen assays. In neurotoxin-induced models, chemicals such as 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat are used to recapitulate the disease. Genetic manipulation of PD-related genes, such as α-Synuclein(SNCA), Leucine-rich repeat kinase 2 (LRRK2), Pten-Induced Kinase 1 (PINK1), Parkin(PRKN), and Protein deglycase (DJ-1) Are used in the transgenic models. An emerging model that combines both genetic- and neurotoxin-based methods has been generated to study the role of the immune system in the pathogenesis of PD. Here, we discuss the advantages and limitations of the different PD models and their utility for different research purposes.

OBJECTIVES: To investigate the use of shortened contrast injection with late triggering in coronary CT angiography (CCTA) for decreasing contrast dose and maintaining image quality. METHODS: 106 patients for CCTA on a 16-cm wide-detector CT were prospectively enrolled into groups A (n = 50) and B (n = 56) randomly. Patient weight-dependent contrast medium (Iopamiro, 370 mgI ml(−1)) at dose rate of 25 mgI/kg/s was used with 8 s and the standard 10 s injection time in groups A and B, respectively. CT values of the aortic sinus (AS), right coronary artery, left anterior descending and left circumflex at the proximal, middle and distal segments were measured and compared. Subjective image quality was evaluated and analyzed with Fisher exact test. Contrast dose, injection rate and enhancement duration (between the start of enhancement in AS and scan finish) were also compared. RESULTS: There was no difference in the injection rate and enhancement duration between the two groups (p > 0.05), while the total contrast dose in group A (36.2 ± 5.7 ml) was significantly lower than in group B (46.4 ± 6.3 ml) (p < 0.001). There was no difference for CT values in all major coronary vessels between the two groups and no difference in subjective image quality scores (all p > 0.05). CONCLUSION: It is feasible to shorten contrast injection to 8 s in CCTA on wide-detector CT systems to significantly reduce contrast dosage, maintain adequate enhancement and reduce contrast-related artifacts. ADVANCES IN KNOWLEDGE: (1) Coronary CT angiography (CCTA) scans with shortened contrast medium injection duration and late triggering are feasible with a 16-cm wide-detector CT system (2) Compared with the conventional CCTA with 10 s contrast injection duration, the new contrast injection protocol of using shortened injection duration (to 8 s) and late triggering reduces contrast dose to 36.2 ml, while maintaining adequate enhancement in vessels and reducing contrast-related artifacts.

To investigate the correlation of all exone mutation in MLAA-34 gene with chemotherapeutic efficacy for leukemia.The expression level of MLAA-34 gene in 40 patients with AML-M5 and 5 healthy volunteers as control was detected by RT-PCR and its effect on chemotherapeutic efficacy were analyzed by RT-PCR; the effect of MLAA-34 gene mutation on overall survival (OS) and progression-free survival (PFS) of AML-M5 patients was analyzed by sequencing of all 12 exoues in MLAA-34 gene, the correlation between the mutation of prognostic genes important to leukemia and the mutation of MLAA-34 gene was explored.The expression level of MLAA-34 gene was significantly up-regulated as compared with that of healthy volunteers, moreover this up-regulation was related with a C59T SNP site located in second exon of MLAA-34 gene, meanswhile this SNP site is affinitive to the well-known mdecular markers of AML, inclinding Fms-like tyrosine kinase (FLT-3) and DNA methyltransferase-3A(DNAMT3A). The AML-M5 patients with high expression of MLAA-34 gene poorly responded to chemotherapy, the AML-M5 patients with MLAA-34 C59T mulation had even more high expression of MLAA-34 gene and significantly short OS and PFS in comparison with those of patients without C59T mutation.The C59T mutation in MLAA-34 gene is a high risk factor for recurrence of AML, and may be a cadidate target for treatment of AML.

// Ying Shi 1 , Guo-Bin Chen 1 , Xiao-Xiao Huang 1 , Chuan-Xing Xiao 1 , Huan-Huan Wang 1 , Ye-Sen Li 6,7 , Jin-Fang Zhang 4 , Shao Li 8 , Yin Xia 4,5 , Jian-Lin Ren 1 and Bayasi Guleng 1,2,3 1 Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, Fujian Province, China 2 Faculty of Clinical Medicine, Medical College, Xiamen University, Xiamen, Fujian Province, China 3 State Key Laboratory of Cellular Stress Biology, Xiamen University, Xiamen, Fujian Province, China 4 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China 5 School of Biomedical Sciences Core Laboratory, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen, China 6 Department of Nuclear Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian Province, China 7 Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, Fujian Province, China 8 MOE Key Laboratory of Bioinformatics, Tsinghua University, Beijing, China Correspondence to: Bayasi Guleng, email: // Jian-Lin Ren, email: // Yin Xia, email: // Keywords: dragon, colorectal cancer, BMP, Smad1/5/8, Erk1/2, proliferation Received : January 11, 2015 Accepted : April 21, 2015 Published : May 12, 2015 Abstract Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer death. However, the molecular mechanisms underlying CRC initiation, growth and metastasis are poorly understood. Dragon (RGMb), a member of the repulsive guidance molecule (RGM) family, has been recently identified as a co-receptor for bone morphogenetic protein (BMP) signaling, but the role of Dragon in CRC development is undefined. Here, we show that Dragon expression was increased in colon cancer tissues compared to control tissues in CAC mouse model and in human patients. Dragon promoted proliferation of CT26.WT and CMT93 colon cancer cells and accelerated tumor growth in the xenograft mouse model. Dragon’s action on colon cancer development was mediated via the BMP4-Smad1/5/8 and Erk1/2 pathways. Therefore, our results have revealed that Dragon is a novel gene that promotes CRC growth through the BMP pathway. Dragon may be exploited as a potential therapeutic target for CRC treatment.

SUMMARY Besides the classical motor symptoms, Parkinson's disease (PD) patients experience a wide range of nonmotor symptoms (NMS) throughout the disease course. However, due to the lack of recognition and understanding of the pathogenesis, NMS symptoms may be overlooked. Familial PD is a well-defined group that can provide a good model to investigate the mechanisms for both motor and NMS in PD. Some studies suggest that the frequency of NMS is not different between genetic and sporadic form of PD while others suggest that specific domains (such as neuropsychiatric symptoms) are more common in the genetic form. Early recognition of NMS may facilitate early diagnosis and monitoring of both sporadic and genetic PD.

Primary breast tuberculosis is rare. We report a case of bilateral primary breast tuberculosis. The patient received incisional drainage and debridement of both breasts. Histopathology of the breast tissues revealed chronic granulomatous inflammation and positive acid-fast stain. The patient received antitubercular therapy for 18 months, and she achieved complete resolution.

Summary: Though genetic data suggest that Polycomb group proteins (PcGs) are central chromatin modifiers and repressors that have been implicated in control of embryonic stem cell (ESC) pluripotency, the precise mechanism of PcG complex recruitment remains elusive, especially in mammals. We now report that the first and second MBT repeats of L3mbtl2 are important structural and functional features that are necessary and sufficient for L3mbtl2-mediated recruitment of PRC1.6 complex to target promoters. Interestingly, this region of L3mbtl2 harbors the evolutionarily conserved Pho-binding pocket also present in Drosophila Sfmbt, and mutation of the critical residues within this pocket completely abolishes its interaction with target promoters. Additionally, decreased PRC1.6 chromatin occupancy was observed following loss of individual components (L3mbtl2, Pcgf6, and Max) of the complex. Our findings suggest that the recruitment of noncanonical PRC1.6 complex in ESCs might be the result of L3mbtl2’s interaction with multiple components of the complex. : Yikai et al. report that Polycomb group protein L3mbtl2 assembles a complex whose composition is conserved with the Drosophila PhoRC. L3mbtl2-mediated chromatin recruitment of a variant PRC1 requires cooperation among complex components. Keywords: Polycomb, PRC1, PRC1.6, L3mbtl2, Pcgf6, Max, Mga, PhoRC, Sfmbt, Ring1b

Both extrinsic and intrinsic tissues contribute to tendon repair, but the origin and molecular functions of extrinsic tissues in tendon repair are not fully understood. Here we show that tendon sheath cells harbor stem/progenitor cell properties and contribute to tendon repair by activating Hedgehog signaling. We found that Osteocalcin (Bglap) can be used as an adult tendon-sheath-specific marker in mice. Lineage tracing experiments show that Bglap-expressing cells in adult sheath tissues possess clonogenic and multipotent properties comparable to those of stem/progenitor cells isolated from tendon fibers. Transplantation of sheath tissues improves tendon repair. Mechanistically, Hh signaling in sheath tissues is necessary and sufficient to promote the proliferation of Mkx-expressing cells in sheath tissues, and its action is mediated through TGFβ/Smad3 signaling. Furthermore, co-localization of GLI1+ and MKX+ cells is also found in human tendinopathy specimens. Our work reveals the molecular function of Hh signaling in extrinsic sheath tissues for tendon repair.

Our laboratory previously used the SEREX method in U937 cells and identified a novel leukemia-associated gene MLAA-34, a novel splice variant of CAB39L associated with acute monocytic leukemia, that exhibited anti-apoptotic activities in U937 cells. Whether MLAA-34 has an anti-apoptotic role in other tumor cells has not yet been reported. We explored whether MLAA-34 exhibited anti-apoptotic effects in HeLa cervical cancer cells and the possible mechanism of action. We generated a HeLa cell line stably expressing MLAA-34 and found that MLAA-34 overexpression had no effect on the growth, apoptosis and cell cycle of HeLa cells. However, upon treatment with arsenic trioxide (ATO) to induce apoptosis, the cell viability and colony formation ability of ATO-treated MLAA-34 stable HeLa cells were significantly higher than that of ATO-treated controls, and the apoptosis rate and proportion of G2/M cells also decreased. We found that ATO treatment of HeLa cells resulted in significant decreases in the expression of β-catenin mRNA and protein and the downstream target factors c-Myc, cyclin B1, and cyclin D1 in the Wnt signaling pathway. Notably, ATO-treated MLAA-34 stable HeLa cells showed a significant reduction in the ATO-mediated downregulation of these factors. In addition, MLAA-34 overexpression significantly increased the expression of nuclear β-catenin protein in ATO-treated cells compared with HeLa cells treated only with ATO. Thus, here we have found that the Wnt/β-catenin signaling pathway is involved in ATO-induced apoptosis in HeLa cells. MLAA-34 reduces ATO-induced apoptosis and G2/M arrest, and the anti-apoptotic effect may be achieved by activating the Wnt/β-catenin signaling pathway in HeLa cells.

OBJECTIVE: To investigate the effect of air pollution on respiratory health in school-aged children in the main urban area of Chongqing, China. METHODS: The main urban area of Chongqing was divided into polluted area and clean area according to the air pollution data shown on the Environmental Protection Agency Website of Chongqing between 2010 and 2015. A cluster sampling method was used to select 695 third-or fourth-grade children from 2 primary schools in the clean or polluted area as study subjects, with 313 children from the clean area and 382 children from the polluted area. Pulmonary function was examined for all children and a standard American epidemiological questionnaire (ATS-DLD-78-C) was used to investigate the prevalence of respiratory diseases and symptoms. RESULTS: Compared with the clean area, the polluted area had significantly higher concentrations of inhalable particles (PM(10)), fine particulate matter (PM(2.5)), and nitric oxide (NO(X)) (P < 0.05). The multivariate logistic regression analysis was performed after adjustment for confounding factors, and the results showed that compared with those in the clean area, the children in the polluted area had significantly higher risks of cough (OR=1.644), cough during cold (OR=1.596), expectoration during cold (OR=2.196), persistent expectoration (OR=1.802), and wheezing (OR=2.415). The boys and girls in the clean area had significantly higher forced vital capacity and forced expiratory volume in one second than those in the polluted area (P < 0.05). CONCLUSIONS: Air pollution in the main urban area of Chongqing is associated with the increased prevalence of respiratory symptoms in school-aged children and has certain effect on children's pulmonary function.

OBJECTIVES This study seeks to examine the characteristics and health-related quality of life (HRQL) of patients with uremic peripheral neuropathy. METHODS Uremic patients undergoing maintenance hemodialysis (MHD) at our hospital were enrolled in this study. Data collection began in January 2011 and ended in June 2011. The patients were divided into two groups, the lesion group (110 cases) and the non-lesion group (168 cases), based on the presence or absence of peripheral neuropathy. To examine continuous changes in signs and symptoms in the lesion group, electromyography (EMG) was performed to measure sensory nerve conduction velocity (SCV), motor nerve conduction velocity (MCV), and distal latency (DL). Furthermore, HRQL was analyzed using the generic Short Form-36 (SF-36) questionnaire. RESULTS Numbness and a burning sensation in the distal limbs were observed in the lesion group; in particular, these phenomena occurred in the upper limbs and the lower limbs in 3.6% (4/110) and 48.2% (53/110) of patients, respectively. With respect to motor symptoms, upper and lower limb weakness was observed in 1.8% (2/110) and 11.8% (13/110) of patients, respectively. Changes in physical signs were mainly evidenced by tendon reflexes, for example, areflexia, or tendon reflex loss was detected in the upper extremities, the knee tendon, and the Achilles tendon in 9.09% (10/110), 55.45% (61/110), and 35.5% (39/110) of patients, respectively. Relative to the non-lesion group, the lesion group had significantly slower average SCV and MCV as well as a longer average DL (p

Mutations in HFE are the most common cause of hereditary hemochromatosis (HH). HFE mutations result in reduced expression of hepcidin, a hepatic hormone, which negatively regulates iron absorption from the duodenum and iron release from macrophages. However, the mechanism by which HFE regulates hepcidin expression in hepatocytes is not well understood. It is known that the bone morphogenetic protein (BMP) pathway plays a central role in controlling hepcidin expression in the liver. Here we show that HFE overexpression increased Smad1/5/8 phosphorylation and hepcidin expression, whereas inhibition of BMP signaling abolished HFE-induced hepcidin expression in Hep3B cells. HFE was found to associate with ALK3, inhibiting ALK3 ubiquitination and proteasomal degradation and increasing ALK3 protein expression and accumulation on the cell surface. The 2 HFE mutants associated with HH, HFE C282Y and HFE H63D, regulated ALK3 protein ubiquitination and trafficking differently, but both failed to increase ALK3 cell-surface expression. Deletion of Hfe in mice resulted in a decrease in hepatic ALK3 protein expression. Our results provide evidence that HFE induces hepcidin expression via the BMP pathway: HFE interacts with ALK3 to stabilize ALK3 protein and increase ALK3 expression at the cell surface.