AHR signaling pathway mediates mitochondrial oxidative phosphorylation which leads to cytarabine resistance.

The aryl hydrocarbon receptor (AHR) has been identified as a significant driver of tumorigenesis. However, its clinical significance in acute myeloid leukemia (AML) remains largely unclear. In this study, RNA-Seq data from AML patients (bone marrow samples from 173 newly diagnosed AML patients) obtained from the TCGA database, and normal human RNA-Seq data (bone marrow samples from 70 healthy individuals) obtained from the GTEX database are downloaded for external validation and complementarity. The data analysis reveals that the AHR signaling pathway is activated in AML patients. Furthermore, there is a correlation between the expressions of AHR and mitochondrial oxidative phosphorylation genes. In vitro experiments show that enhancing AHR expression in AML cells increases mitochondrial oxidative phosphorylation and induces resistance to cytarabine. Conversely, reducing AHR expression in AML cells decreases cytarabine resistance. These findings deepen our understanding of the AHR signaling pathway's involvement in AML.

Simultaneous rectal neuroendocrine tumors and pituitary adenoma: A case report and review of literature.

BACKGROUND: Neuroendocrine tumors (NET) are rare heterogeneous tumors that arise from neuroendocrine cells throughout the body. Acromegaly, a rare and slowly progressive disorder, usually results from a growth hormone (GH)-secreting pituitary adenoma. CASE SUMMARY: We herein describe a 38-year-old patient who was initially diagnosed with diabetes. During colonoscopy, two bulges were identified and subsequently removed through endoscopic submucosal dissection. Following the surgical intervention, the excised tissue samples were examined and confirmed to be grade 2 NET. 18F-ALF-NOTATATE positron emission tomography-computed tomography (PET/CT) and 68Ga-DOTANOC PET/CT revealed metastases in the peri-intestinal lymph nodes, prompting laparoscopic low anterior resection with total mesorectal excision. The patient later returned to the hospital because of hyperglycemia and was found to have facial changes, namely a larger nose, thicker lips, and mandibular prognathism. Laboratory tests and magnetic resonance imaging (MRI) suggested a GH-secreting pituitary adenoma. The pituitary adenoma shrunk after treatment with octreotide and was neuroendoscopically resected via a trans-sphenoidal approach. Whole-exome sequencing analysis revealed no genetic abnormalities. The patient recovered well with no evidence of recurrence during follow-up. CONCLUSION: 18F-ALF-NOTATE PET/CT and MRI with pathological analysis can effectively diagnose rare cases of pituitary adenomas complicated with rectal NET.

[Construction of a predictive model for early acute kidney injury risk in intensive care unit septic shock patients based on machine learning].

OBJECTIVE: To analyze the risk factors of acute kidney injury (AKI) in patients with septic shock in intensive care unit (ICU), construct a predictive model, and explore the predictive value of the predictive model. METHODS: The clinical data of patients with septic shock who were hospitalized in the ICU of the Affiliated Hospital of Jining Medical College from April 2015 to June 2019 were retrospectively analyzed. According to whether the patients had AKI within 7 days of admission to the ICU, they were divided into AKI group and non-AKI group. 70% of the cases were randomly selected as the training set for building the model, and the remaining 30% of the cases were used as the validation set. XGBoost model was used to integrate relevant parameters to predict the risk of AKI in patients with septic shock. The predictive ability was assessed through receiver operator characteristic curve (ROC curve), and was correlated with acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), procalcitonin (PCT) and other comparative verification models to verify the predictive value. RESULTS: A total of 303 patients with septic shock were enrolled, including 153 patients with AKI and 150 patients without AKI. The incidence of AKI was 50.50%. Compared with the non-AKI group, the AKI group had higher APACHE II score, SOFA score and blood lactate (Lac), higher dose of norepinephrine (NE), higher proportion of mechanical ventilation, and tachycardiac. In the XGBoost prediction model of AKI risk in septic shock patients, the top 10 features were serum creatinine (SCr) level at ICU admission, NE use, drinking history, albumin, serum sodium, C-reactive protein (CRP), Lac, body mass index (BMI), platelet count (PLT), and blood urea nitrogen (BUN) levels. Area under the ROC curve (AUC) of the XGBoost model for predicting the risk of AKI in patients with septic shock was 0.816, with a sensitivity of 73.3%, a specificity of 71.7%, and an accuracy of 72.5%. Compared with the APACHE II score, SOFA score and PCT, the performance of the model improved significantly. The calibration curve of the model showed that the goodness of fit of the XGBoost model was higher than the other scores (the calibration curve had the lowest score, with a score of 0.205). CONCLUSIONS: Compared with the commonly used clinical scores, the XGBoost model can more accurately predict the risk of AKI in patients with septic shock, which helps to make appropriate diagnosis, treatment and follow-up strategies while predicting the prognosis of patients.

[The Changes of Peripheral Blood Fâ «a-AT, TSP-1, LA Ratio in Patients with Systemic Lupus Erythematosus and the Clinical Value of Combined Diagnosis of Thrombotic Events].

OBJECTIVE: To explore the changes of Ⅻ antithrombin (FⅫa-AT), thrombospondin-1 (TSP-1), and lupus anticoagulant (LA) ratio in the peripheral blood factor of patients with systemic lupus erythematosus (SLE) and the clinical value of combined diagnosis of thrombotic events. METHODS: A total of 133 SLE patients treated in Xingtai People's Hospital were selected and divided into simple SLE group (105 cases) and SLE complicated with thrombosis group (28 cases) according to whether thrombotic events occurred, and 102 cases of healthy people in the same period were selected as control. The clinical data of the 3 groups, the level of peripheral blood FⅫa-AT, TSP-1, and LA ratio were compared, the relationship between each peripheral blood index and SLE disease activity index (SLEDAI) score were analyzed. The influencing factors of thrombotic events in SLE patients were analyzed, and the value of each peripheral blood index in the diagnosis of SLE complicated with thrombotic events were evaluated. RESULTS: The proportion of the patients with age ≥60 year, hypertension, and smoking history in SLE complicated with thrombosis group was higher than those in simple SLE group and control group (P＜0.05). The SLEDAI score, peripheral blood FⅫa-AT, TSP-1, LA ratio levels of the patients in SLE complicated with thrombosis group were significantly higher than those in simple SLE group and control group, and the simple SLE group was significantly higher than the control group (P＜0.05). FⅫa-AT, TSP-1, LA ratio in peripheral blood of SLE patients were positively correlated with SLEDAI score (r=0.663, 0.578 and 0.625). Age, blood pressure, smoking history, peripheral blood FⅫa-AT, TSP-1, LA ratio were the important influencing factors of thrombotic events in SLE patients (P＜0.05). The AUC diagnosed by the FⅫa-AT, TSP-1, and LA ratio in peripheral blood was 0.881, the 95% CI was 0.813-0.931, the sensitivity was 82.14%, and the specificity was 91.43%, which was superior to each index alone (P＜0.05). CONCLUSION: Peripheral blood FⅫa-AT, TSP-1, LA ratio level changes in SLE patients are significantly related to disease activity, and the combined diagnosis of thrombotic events is more reliable.

Curcumin attenuates inflammation of Macrophage-derived foam cells treated with Poly-L-lactic acid degradation via PPARγ signaling pathway.

Poly-L-lactic acid (PLLA) is considered to be a promising candidate material for biodegradable vascular scaffolds (BVS) in percutaneous coronary intervention (PCI). But, PLLA-BVS also faces the challenge of thrombosis (ST) and in-stent restenosis (ISR) caused by in-stent neo-atherosclerosis (ISNA) associated with inflammatory reactions in macrophage-derived foam cells. Our previous studies have confirmed that curcumin alleviates PLLA-induced injury and inflammation in vascular endothelial cells, but it remains unclear whether curcumin can alleviate the effect of inflammatory reactions in macrophage-derived foam cells while treated with degraded product of PLLA. In this study, PLLA-BVS was implanted in the porcine coronary artery to examine increased macrophages and inflammatory cytokines such as NF-κb and TNF-α by histology and immunohistochemistry. In vitro, macrophage-derived foam cells were induced by Ox-LDL and observed by Oil Red Staining. Foam cells were treated with pre-degraded PLLA powder, curcumin and PPARγ inhibitor GW9662, and the expression of IL-6, IL-10, TNF-α, NF-κb, PLA2 and PPARγ were investigated by ELISA or RT-qPCR. This study demonstrated that the macrophages and inflammatory factors increased after PLLA-BVS implantation in vivo, and foam cells derived from macrophages promoted inflammation by products of PLLA degradation in vitro. This present study was found that the inflammation of foam cells at the microenvironment of PLLA degraded products were significantly increased, and curcumin can attenuate the inflammation caused by the PLLA degradation via PPARγ signal pathway. In addition, curcumin should be further studied experimentally in vivo experiments on animal models as a potential therapeutic to reduce ISNA of PLLA-BVS. Graphical abstract.

EZH2 suppresses insulinoma development by epigenetically reducing KIF4A expression via H3K27me3 modification.

Kinesin family member 4A (KIF4A), located in the human chromosome band Xq13.1, is aberrantly overexpressed in various cancers. Our study intended to assess the expression of KIF4A in insulinoma and to gain new insights into the molecular mechanisms of this rare disease. First, KIF4A was significantly recruited in pancreatic endocrine cells relative to other cell types. A significant correlation existed between the overexpression of KIF4A and the poor survival of pancreatic adenocarcinoma patients. As revealed by CCK-8, TUNEL assay, flow cytometry, wound healing, Matrigel-transwell, senescence-associated ß-galactosidase staining, ELISA, and subcutaneous tumor formation analysis in nude mice, knocking down KIF4A significantly inhibited the growth and metastasis of insulinoma cells in vivo and in vitro. Mechanistically, we observed that KIF4A promoter sequences had reduced H3K27me3 modifications, and decline in enhancer of zeste homolog-2 (EZH2) expression promoted KIF4A expression by reducing the modification, thus leading to insulinoma. Moreover, EZH2 knockdown-induced insulinoma cell proliferation was dependent on KIF4A overexpression since KIF4A knockdown eradicated shEZH2-induced proliferation of insulinoma cells. In summary, KIF4A was identified as a possible therapeutic target for insulinoma.

Systematic Characterization of the Biodistribution of the Oncolytic Virus M1.

Oncolytic viruses are emerging as important tools for immunotherapy for cancer treatment; however, most of the clinically tested oncolytic candidates are still administered by intratumoral injection, and new viruses capable of intravenous injection are urgently needed. The M1 virus is a positive-sense single-stranded RNA virus that belongs to the alphavirus family, and it was identified as an oncolytic virus that can selectively replicate in and kill tumor cells after intravenous injection. To further develop M1 for clinical research through intravenous injection, we systematically investigated the biodistribution characteristics of the M1 virus in normal rats, cynomolgus monkeys, and tumor-bearing immunocompromised mice. The data showed that the M1 virus was eliminated gradually from normal tissue but replicated and increased rapidly in tumor tissue. More importantly, the virus also infiltrated the blood-brain barrier and specifically replicated in and killed malignant glioma in immunocompetent mice. Our data proved the tumor selectivity and safety of the M1 virus, supporting its further clinical development.

microRNA-124-3p inhibits tumourigenesis by targeting mitogen-activated protein kinase 4 in papillary thyroid carcinoma.

The study aimed to investigate the role of miR-124-3p and its potential molecular mechanism in papillary thyroid cancer (PTC). The expression of miR-124-3p and mitogen-activated protein kinase 4 (MAP2K4) in human thyroid follicular epithelial cell line (NTHY-ORI3-1) and human papillary thyroid carcinoma cell lines (SW1736, BCPAP, TPC-1 and K1) was measured by RT-qPCR. Cell proliferation was measured by CCK-8, while cell cycle and apoptosis rate were measured by flow cytometry. Invasive ability and migrative ability were measured by transwell assay and wound healing assay, respectively. Western blot was used to detect the levels of relative proteins. In vivo, TPC-1 cells transfected with miR-124-3p mimic were subcutaneously injected into the flank of the mice to form tumour. After successful modelling, mice were divided into two groups (n = 10): Control group and miR-124-3p mimic group. The present study showed that miR-124-3p was lowly expressed, while MAP2K4 was highly expressed in PTC cell lines. Besides, miR-124-3p targeted MAP2K4 and negatively regulated MAP2K4 in TPC-1 cells. In addition, miR-124-3p inhibited the proliferation and motility, and induced apoptosis and cell cycle arrest of TPC-1 cells by inactivating MAP2K4/JNK/JunD pathway. Furthermore, miR-124-3p inhibited tumour formation by downregulating MAP2K4 level in vivo. In conclusion, the study provided a novel molecular mechanism of miR-124-3p in the progress of PTC. SIGNIFICANCE OF THE STUDY: Papillary thyroid cancer (PTC) is the most important pathological type of thyroid cancer, accounting for 80% of thyroid cancer. miR-124-3p exhibited significant inhibitory role in the transformation and development of malignant tumours. However, in PTC, the roles and its potential molecular mechanism are unclear. Here, the study investigated the roles of miR-124-3p in the progress of PTC and its potential molecular mechanism. We found that miR-124-3p inhibited the proliferation and motility, and induced apoptosis and cell cycle arrest in PTC cells. This study provided a novel molecular mechanism of miR-124-3p in the progress of PTC.

Efficacy of neuroendoscopic surgery versus craniotomy for supratentorial hypertensive intracerebral hemorrhage: A meta-analysis of randomized controlled trials.

BACKGROUND: Hypertensive cerebral hemorrhage (HCH) is a potentially life-threatening neurological condition with an extremely high morbidity and mortality. In recent years, neuroendoscopy has been used to treat intracerebral hemorrhage (ICH). However, the choice of neuroendoscopic surgery versus craniotomy for patients with intracerebral hemorrhages is controversial. AIM: We conducted this meta-analysis to assess the efficacy of neuroendoscopic surgery compared with craniotomy in patients with supratentorial hypertensive ICH. METHODS: A systematic electronic search was conducted of online electronic databases: PubMed, Embase, and the Cochrane Library updated on December 2017. The meta-analysis only included randomized controlled studies. RESULTS: Three randomized controlled trials met our inclusion criteria. The pooled analysis of death showed that neuroendoscopic surgery decreased the rate of death when compared with craniotomy (RR = 0.58, 95% CI 0.26-1.29; p = .18). The pooled result of complications indicated that neuroendoscopic surgery has a tendency toward lower complications (RR = 0.37, 95% CI 0.28-0.49; p < .001). CONCLUSIONS: Our results suggested that neuroendoscopic surgery has lower complications, but no superior advantages in morbidity rates. Since the advantage of neuroendoscopic surgery has been performed in some area, the continuation of multi-center comparative investigation with craniotomy may be necessary. Moreover, some efforts need to be taken in selecting appropriate patients with different treatments.

Single nucleotide polymorphism rs2555639 in 15-PGDH and colorectal cancer metastasis.

PURPOSE: To investigate the correlation between metastasis of colon cancer and the single nucleotide polymorphism (SNP) rs2555639 in nicotinamide adenine dinucleotide (NAD)+-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH) (rs2555639). METHODS: We investigated the genotyping of peripheral blood genomic DNA in patients using the TaqMan probe method. The relationship between the genotype of 15-PGDH (rs2555639) and metastasis of colon cancer was analyzed. RESULTS: We noticed that rs2555639 TT polymorphism was significantly correlated with the susceptibility to colon cancer metastasis. Also, in the stratified analysis, we found similar results. CONCLUSION: Our data suggested that the rs2555639 T allele is associated with increased risk of metastasis of colon cancer, which can be used as an indicator for colon cancer metastasis.

Prescription practices in the treatment of agitation in newly hospitalized Chinese schizophrenia patients: data from a non-interventional naturalistic study.

BACKGROUND: Data on the pharmacological management of acute agitation in schizophrenia are scarce. The aim of this study is to investigate the prescription practices in the treatment of agitation in Chinese patients with schizophrenia. METHODS: We conducted a large, multicenter, observational study in 14 psychiatry hospitals in China. Newly hospitalized schizophrenia patients with the PANSS-EC total score ≥ 14 and a value ≥4 on at least one of its five items were included in the study. Their drug treatments of the first 2 weeks in hospital were recorded by the researchers. RESULTS: Eight hundred and 53 patients enrolled in and 847 (99.30%) completed the study. All participants were prescribed antipsychotics, 40 (4.72%) were prescribed benzodiazepine in conjunction with antipsychotics and 81 were treated with modified electric convulsive therapy (MECT). Four hundred and 12 (48.64%) patients were prescribed only one antipsychotic, in the order of olanzapine (120 patients, 29.13%), followed by risperidone (101 patients, 24.51%) and clozapine (41 patients, 9.95%). About 435 (51.36%) participants received antipsychotic polypharmacy, mostly haloperidol + risperidone (23.45%), haloperidol+ olanzapine (17.01%), olanzapine+ ziprasidone (5.30%), haloperidol + clozapine (4.37%) and haloperidol + quetiapine (3.90%). Binary logistic regression analysis suggests that a high BARS score (OR 2.091, 95%CI 1.140-3.124), severe agitation (OR 1.846, 95%CL 1.266-2.693), unemployment or retirement (OR 1.614, 95%CL 1.189-2.190) and aggressiveness on baseline (OR 1.469, 95%CL 1.032-2.091) were related to an increased antipsychotic polypharmacy odds. Male sex (OR 0.592, 95%CL 0.436-0.803) and schizophrenia in older persons (age ≥ 55 years, OR 0.466, 95%CL 0.240-0.902) were less likely to be associated with antipsychotic polypharmacy. CONCLUSION: The present study demonstrates that monotherapy and polypharmacy display equally common patterns of antipsychotic usage in managing agitation associated with schizophrenia in China. The extent and behavioral activities of agitation and several other factors were associated with polypharmacy.

The Influence of Envelope C-Terminus Amino Acid Composition on the Ratio of Cell-Free to Cell-Cell Transmission for Bovine Foamy Virus.

Foamy viruses (FVs) have extensive cell tropism in vitro, special replication features, and no clinical pathogenicity in naturally or experimentally infected animals, which distinguish them from orthoretroviruses. Among FVs, bovine foamy virus (BFV) has undetectable or extremely low levels of cell-free transmission in the supernatants of infected cells and mainly spreads by cell-to-cell transmission, which deters its use as a gene transfer vector. Here, using an in vitro virus evolution system, we successfully isolated high-titer cell-free BFV strains from the original cell-to-cell transmissible BFV3026 strain and further constructed an infectious cell-free BFV clone called pBS-BFV-Z1. Following sequence alignment with a cell-associated clone pBS-BFV-B, we identified a number of changes in the genome of pBS-BFV-Z1. Extensive mutagenesis analysis revealed that the C-terminus of envelope protein, especially the K898 residue, controls BFV cell-free transmission by enhancing cell-free virus entry but not the virus release capacity. Taken together, our data show the genetic determinants that regulate cell-to-cell and cell-free transmission of BFV.

The effect of bovine BST2A1 on the release and cell-to-cell transmission of retroviruses.

BACKGROUND: Human BST2 (hBST2, also called Tetherin) is a host restriction factor that blocks the release of various enveloped viruses. BST2s from different mammals also possess antiviral activity. Bovine BST2s (bBST2s), bBST2A1 and bBST2A2, reduce production of cell-free bovine leukemia virus (BLV) and vesicular stomatitis virus (VSV). However, the effect of bBST2 on other retroviruses remains unstudied. RESULTS: Here, we studied the antiviral activity of wildtype and mutant bBST2A1 proteins on retroviruses including human immunodeficiency virus type 1 (HIV-1), prototypic foamy virus (PFV), bovine foamy virus (BFV) and bovine immunodeficiency virus (BIV). The results showed that wildtype bBST2A1 suppressed the release of HIV-1, PFV and BFV. We also generated bBST2A1 mutants, and found that GPI anchor and dimerization, but not glycosylation, are essential for antiviral activity of bBST2A1. Moreover, unlike hBST2, bBST2A1 displayed no inhibitory effect on cell-to-cell transmission of PFV, BFV and BIV. CONCLUSIONS: Our data suggested that bBST2A1 inhibited retrovirus release, however, had no effect on cell-to-cell transmission of retroviruses.

A nanoporous Ag(i) coordination polymer for selective adsorption of carcinogenic dye Acid Red 26.

A cationic Ag(i) coordination polymer with 1D nanoporous channels (ca. 1.22 nm diameter) shows the selective and complete removal of carcinogenic dye Acid Red 26 from aqueous solution upon the size-exclusion and charge-matching effect.

Important role of N108 residue in binding of bovine foamy virus transactivator Tas to viral promoters.

BACKGROUND: Bovine foamy virus (BFV) encodes the transactivator BTas, which enhances viral gene transcription by binding to the long terminal repeat promoter and the internal promoter. In this study, we investigated the different replication capacities of two similar BFV full-length DNA clones, pBS-BFV-Y and pBS-BFV-B. RESULTS: Here, functional analysis of several chimeric clones revealed a major role for the C-terminal region of the viral genome in causing this difference. Furthermore, BTas-B, which is located in this C-terminal region, exhibited a 20-fold higher transactivation activity than BTas-Y. Sequence alignment showed that these two sequences differ only at amino acid 108, with BTas-B containing N108 and BTas-Y containing D108 at this position. Results of mutagenesis studies demonstrated that residue N108 is important for BTas binding to viral promoters. In addition, the N108D mutation in pBS-BFV-B reduced the viral replication capacity by about 1.5-fold. CONCLUSIONS: Our results suggest that residue N108 is important for BTas binding to BFV promoters and has a major role in BFV replication. These findings not only advances our understanding of the transactivation mechanism of BTas, but they also highlight the importance of certain sequence polymorphisms in modulating the replication capacity of isolated BFV clones.

Niche Regulation of Limbal Epithelial Stem Cells: Relationship between Inflammation and Regeneration.

Human limbal palisades of Vogt are the ideal site for studying and practicing regenerative medicine due to their accessibility. Nonresolving inflammation in limbal stroma is common manifestation of limbal stem cell (SC) deficiency and presents as a threat to the success of transplanted limbal epithelial SCs. This pathologic process can be overcome by transplantation of cryopreserved human amniotic membrane (AM), which exerts anti-inflammatory, antiscarring and anti-angiogenic action to promote wound healing. To determine how AM might exert anti-inflammation and promote regeneration, we have purified a novel matrix, HC-HA/PTX3, responsible for the efficacy of AM efficacy. HC-HA complex is covalently formed by hyaluronan (HA) and heavy chain 1 (HC1) of inter-α-trypsin inhibitor by the catalytic action of tumor necrosis factor-stimulated gene-6 (TSG-6) and are tightly associated with pentraxin 3 (PTX3) to form HC-HA/PTX3. In vitro reconstitution of the limbal niche can be established by reunion between limbal epithelial progenitors and limbal niche cells on different substrates. In 3-dimensional Matrigel, clonal expansion indicative of SC renewal is correlated with activation of canonical Wnt signaling and suppression of canonical bone morphogenetic protein (BMP) signaling. In contrast, SC quiescence can be achieved in HC-HA/PTX3 by activation of canonical BMP signaling and non-canonical planar cell polarity (PCP) Wnt signaling, but suppression of canonical Wnt signaling. HC-HA/PTX3 is a novel matrix mitigating nonresolving inflammation and restoring SC quiescence in the niche for various applications in regenerative medicine.

[The hearing and vestibular evoked myogenic potentials test in patients with primary benign paroxysmal positional vertigo].

OBJECTIVE: To investigate the result of vestibular evoked myogenic potentials (VEMP) of primary benign paroxysmal positional vertigo(BPPV)and to identify the characteristics in VEMP examination of the primary BPPV and to observe the relevance of patients with primary BPPV and abnormal VEMP with hearing loss. METHOD: Patients with primary BPPV were tested with pure tone audiometry, videonystagmograph and VEMPs test. We analyzed the difference in the two groups with normal hearing and hearing loss, discussed the etiology and pathogenesis. RESULT: Primary BPPV comprised 23.0% with hearing lost, 77.0% hearing normal. The results of oVEMP were abnormal in 79. 7% (59/74) of the cases; and the results of cVEMP were abnormal in 66. 2% (49/74) of the cases; oVEMP and cVEMP differences to the diagnosis of primary BPPV (P<0. 05); oVEMP and cVEMP differences to the diagnosis primary BPPV with hearing lost (P<0. 05). CONCLUSION: oVEMP detection positive rate of primary BPPV is higher than cVEMP,which may be due to otolithic particles falling from the utricle; positive rate of cVEMP in primary BPPV with hearing loss is higher than that of oVEMP, which may related to the cochlear and sacculus occured in the same embryonic tissue structure.

[Clinicopathologic features and prognosis of 51 patients with α-fetoprotein-producing gastric cancer].

OBJECTIVE: To analyze the clinicopathologic features and prognosis of α-fetoprotein (AFP)-producing gastric cancers (AFPGC). METHODS: Fifty-one serum AFP-positive patients with positive immunohistochemical staining of AFP in the primary lesions (study group) and sixty-five gastric cancer cases with normal AFP level (control group) treated in our department from January 2005 to December 2007 were included in this study. Their clinicopathologic features and follow-up data were statistically analyzed. RESULTS: Compared with the control group, the study group had a higher incidence of poorly differentiated adenocarcinoma (P=0.021) and liver metastasis (P=0.001) than that in the control group.The TNM stages in the study group were significantly higher than those in the control group (P=0.001). The 1-, 2-, and 5-year survival rates of the study group were 62.7%, 27.5% and 4.7%, respectively, and the median survival was 16 months, significantly lower than the 84.6%, 55.4%, 16.5%, and 30 months of the control group (P<0.001 for all). The serum AFP levels in the study group ranged from 58.63 µg/L to 12 100.00 µg/L, and could be classified into two groups:27 cases <500 µg/L, and 24 cases ≥500 µg/L. There was no significant difference of the immunohistochemical staining results between the two subgroups (P=0.912). CONCLUSIONS: AFPGC is a special type of gastric cancer with high degree of malignancy and poor prognosis. Monitoring of serum AFP level can earlier detect the progression of disease and give corresponding treatment.

[Cinical and genetic characteristics of familial Meniere's disease: three families report].

OBJECTIVE: To investigate the clinical and genetic characteristics of three Chinese Meniere's disease (MD) families and decipher the mechanism of MD further. METHODS: Personal and family medical evidence of hearing loss, vestibular symptoms, and other clinical abnormalities of the participants were identified, clinical and genetic features were analyzed. Targeted 307 genes capture and high-throughput sequencing were performed on the two ascertained members of family 1007184. RESULTS: Eight patients from these three families showed post-lingual sensorineural hearing loss, six women and two men were involved. Age of onset in these affected members concentrated in the middle age, with the average age of 39.3 years old. Among them, patients from 1407278 were accompanied by migraine. All of the three probands presented as recurrent vertigo firstly, and then fluctuated hearing loss showed up, accompanying by tinnitus and ear fullness feeling. The hearing loss manifested as late-onset, low frequency-involved pattern, with subsequent gradual progression from moderate to severe level. Some of the patients progressed to severe level involving all frequencies at higher ages. In addition, most of the cases showed revitalization. Four cases received vestibular function tests, three of which had varying dysfunction of vestibular function, while the other one had normal vestibular function. Patients who had abnormal vestibular function showed much more severe hearing impairment. The three-generation family 1007193 had an autosomal recessive genetic characteristics, family 1007184 showed autosomal dominant inheritance of characteristics, family 1407278 were either autosomal dominant or X-linked dominant pattern. Through target genes capture high-throughput sequencing technology, we identified two candidate variants in the two members of family 1007184, named c. 2057G>A in EGFLAM and c. 1961C>T in ITGA8. CONCLUSION: Meniere's disease has some genetic and familial aggregation in Chinese population, but its complex genetic pathogenic mechanisms need further study.

Activation of RhoA-ROCK-BMP signaling reprograms adult human corneal endothelial cells.

Currently there are limited treatment options for corneal blindness caused by dysfunctional corneal endothelial cells. The primary treatment involves transplantation of healthy donor human corneal endothelial cells, but a global shortage of donor corneas necessitates other options. Conventional tissue approaches for corneal endothelial cells are based on EDTA-trypsin treatment and run the risk of irreversible endothelial mesenchymal transition by activating canonical Wingless-related integration site (Wnt) and TGF-ß signaling. Herein, we demonstrate an alternative strategy that avoids disruption of cell-cell junctions and instead activates Ras homologue gene family A (RhoA)-Rho-associated protein kinase (ROCK)-canonical bone morphogenic protein signaling to reprogram adult human corneal endothelial cells to neural crest-like progenitors via activation of the miR302b-Oct4-Sox2-Nanog network. This approach allowed us to engineer eight human corneal endothelial monolayers of transplantable size, with a normal density and phenotype from one corneoscleral rim. Given that a similar signal network also exists in the retinal pigment epithelium, this partial reprogramming approach may have widespread relevance and potential for treating degenerative diseases.