Diagnostic Potential of Complementation of MRI to Prenatal Ultrasound for Detecting Orofacial Clefts in High-Risk Fetuses: A Network Meta-Analysis.

OBJECTIVE: To compare the complementation of magnetic resonance imaging (MRI) to prenatal ultrasound (US) with prenatal US alone in detecting orofacial clefts in high-risk fetuses. DESIGN: A network meta-analysis. SETTING: Literature retrieval in PubMed, EMBASE, and Cochrane library, and meta-analysis based on STATA 14.0. PATIENTS: Fetuses were at high-risk for orofacial clefts. INTERVENTIONS: Prenatal US and the complementation of MRI to prenatal US. MAIN OUTCOME MEASURES: The pooled sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), diagnostic odds ratio (DOR), and area under the curve (AUC). RESULTS: Thirteen studies involving 776 patients were included. Direct meta-analysis showed that the complementation of MRI to prenatal US did not differ from prenatal US in detecting orofacial clefts if the type of orofacial clefts was not distinguished. Subgroup analysis showed that the specificity of prenatal US for the detection of isolated cleft palate (CP) was lower than that of the complementation of MRI to prenatal US. Furthermore, network meta-analysis consistently suggested a comparable diagnostic value between prenatal US and the complementation of MRI to prenatal US. Moreover, subgroup analysis showed that the specificity of prenatal US was significantly lower than that of complementation of MRI to prenatal US for the detection of isolated CP. CONCLUSIONS: MRI is more accurate than ultrasound in detecting cleft palate. Therefore, MRI should be offered if there is a fetus with a possible or ultrasound diagnosis of cleft palate, especially if the evaluation of cleft palate is deemed unsatisfactory after careful evaluation of the images.

Targeted exome sequencing strategy (NeoEXOME) for Chinese newborns using a pilot study with 3423 neonates.

BACKGROUND: Newborn screening (NBS) aims to detect congenital anomalies, and next-generation sequencing (NGS) has shown promise in this aspect. However, the NBS strategy for monogenic inherited diseases in China remains insufficient. METHODS: We developed a NeoEXOME panel comprising 601 genes that are relevant to the Chinese population found through extensive research on available databases. An interpretation system to grade the results into positive (high-risk, moderate-risk, and low-risk genotypes), negative, and carrier according to the American College of Medical Genetics (ACMG) guidelines was also developed. We validated the panel to evaluate its efficacy by using data from the "1000 Genomes Project" and conducted a pilot multicenter study involving 3423 neonates. RESULTS: The NGS positive rate in the 1000 Genomes Project was 7.6% (23/301), whereas the rate was 12.0% in the multicenter study, including 3249 recruited neonates. Notably, in 200 neonates, positive per conventional NBS, 58.5% (69/118) showed results consistent with NGS. In the remaining 3049 neonates showing negative results in conventional NBS, 271 (8.9%) were positive per NGS, and nine of them were clinically diagnosed with diseases in the follow-up. CONCLUSION: We successfully designed a NeoEXOME panel for targeted sequencing of monogenic inherited diseases in NBS. The panel demonstrated high performance in the Chinese population, particularly for the early detection of diseases with no biochemical markers.

[Retracted] miR­206 inhibits cancer initiating cells by targeting EHF in gastric cancer.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the colony formation assay data shown in Figs. 2, 4 and 8 were strikingly similar to data that had already appeared in another article written by different authors at different research institutes [Chen W, Wang J, Liu S, Wang S, Cheng Y, Zhou W, Duan C and Zhang C: MicroRNA­361­3p suppresses tumor cell proliferation and metastasis by directly targeting SH2B1 in NSCLC. J Exp Clin Cancer Res 35: 76, 732516, 2016]. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 38: 1688­1694, 2017; DOI: 10.3892/or.2017.5794].

[Prenatal genetic diagnosis for fetuses with anomalies revealed by fetal echocardiography].

OBJECTIVE: To carry out amniocyte karyotyping analysis and chromosomal microarray analysis (CMA) for women with anomalies revealed by fetal echocardiography. METHODS: From January 2019 to December 2021, genetic testing was carried out for 205 fetuses including 97 with soft marker anomalies and 108 with structural heart abnormalities. Among these, 138 only had abnormal fetal echocardiography, whilst 38 and 29 were complicated with extracardiac soft marker anomalies and extracardiac structural malformation, respectively. RESULTS: No significant difference was detected in the detection rate of genetic anomalies between fetuses with heart-related soft markers and those with abnormal heart structures (P > 0.05). Compared with those with abnormal fetal echocardiography alone, the detection rates of chromosomal aneuploidies in those with abnormal extracardiac soft markers or abnormal extracardiac structures were significantly higher (P < 0.05). Twenty-eight chromosomal aneuploidies (including a rare mosaicism), 2 balanced translocations and 1 supernumerary marker chromosome were detected by karyotyping analysis. Twenty-seven aneuploidies, 19 copy number variations (CNVs) and 1 uniparental disomy were detected by CMA. CONCLUSION: Prenatal diagnosis has attached great importance to the suggestive role of fetal heart-related soft markers, and chromosomal aneuploidies are more common among fetuses with abnormal extracardiac soft markers and extracardiac structural abnormalities. Chromosomal Karyotyping is useful for the detection of balanced translocations and mosaicisms. CMA is helpful for the detection of CNVs. Identification of the genetic causes can facilitate genetic counseling for the affected couples.

Degos disease with multiple intestinal perforations: A missed-opportunity case report and literature review.

Introduction: Degos disease, also known as malignant atrophic papulosis (MAP), is a rare systemic obstructive vascular disease with unknown pathophysiology, which can affect multiple systems, especially gastrointestinal tract and central nervous system. Intestinal perforations with MAP is associated with high mortality rate and ambiguous treatment outcomes. Case presentation: Here we report a missed-opportunity case of Degos disease characterized by generalized skin eruption and multiple intestinal perforations. Definite diagnosis of Degos disease was finally concluded after two exploratory laparotomy operations and skin biopsies. Due to the delayed diagnosis and treatment, the patient died after being discharged automatically in spite of application of aspirin and low-dose subcutaneous heparin. In view of such circumstances, we searched the Pubmed using "Degos [Title] OR Malignant Atrophic Papulosis [Title]" AND "perforation [Title] OR perforations [Title]" and make a detailed analysis of the result. Conclusions: Degos disease is a rare systemic obstructive vascular disease with unknown pathologic mechanism and unavailable treatment methods. Diagnosis is usually based on the presence of pathognomonic skin lesions and tissue biopsy. Gastrointestinal involvement can cause serious and lethal conditions with high mortality. Currently, how to achieve a satisfying prognosis of MAP with intestinal perforations becomes the most urgent problem in front of medical staff.

A synonymous mutation in PI4KA impacts the transcription and translation process of gene expression.

Phosphatidylinositol-4-kinase alpha (PI4KIIIα), encoded by the PI4KA gene, can synthesize phosphatidylinositol-4-phosphate (PI-4-P), which serves as a specific membrane marker and is instrumental in signal transduction. PI4KA mutations can cause autosomal recessive diseases involving neurological, intestinal, and immunological conditions (OMIM:619621, 616531, 619708). We detected sepsis, severe diarrhea, and decreased immunoglobulin levels in one neonate. Two novel compound heterozygous mutations, c.5846T>C (p.Leu1949Pro) and c.3453C>T (p.Gly1151=), were identified in the neonate from the father and the mother, respectively. Sanger sequencing and reverse transcription polymerase chain reaction (RT-PCR) for peripheral blood and minigene splicing assays showed a deletion of five bases (GTGAG) with the c.3453C>T variant at the mRNA level, which could result in a truncated protein (p.Gly1151GlyfsTer17). The missense mutation c.5846T>C (p.Leu1949Pro) kinase activity was measured, and little or no catalytic activity was detected. According to the clinical characteristics and gene mutations with functional verification, our pediatricians diagnosed the child with a combined immunodeficiency and intestinal disorder close to gastrointestinal defects and immunodeficiency syndrome 2 (GIDID2; OMIM: 619708). Medicines such as immunomodulators are prescribed to balance immune dysregulation. This study is the first report of a synonymous mutation in the PI4KA gene that influences alternative splicing. Our findings expand the mutation spectrum leading to PI4KIIIa deficiency-related diseases and provide exact information for genetic counseling.

Dietary supplementation of ferrous glycinate improves intestinal barrier function by modulating microbiota composition in Cherry Valley ducks.

Ferrous glycinate (Fe-Gly) has been increasingly used as iron fortification in the diets of weaned piglets and broilers, but the effect of Fe-Gly on intestinal barrier function in meat ducks has not been well defined. This study therefore investigated the effect of Fe-Gly on apparent nutrient utilization, hematological indices, intestinal morphological parameters, intestinal barrier function and microbial composition in meat ducks. A total of 672 one-day-old Cherry Valley ducks were randomly divided into 6 treatments (8 replicates for each treatment and 14 ducks for each replicate) and fed diets with 0 (control), 30, 60, 90 and 120 mg/kg Fe-Gly or 120 mg/kg FeSO4 for 35 d. The results showed that diets supplemented with Fe-Gly significantly increased average daily gain (ADG), average daily feed intake (ADFI), hematocrit (HCT), mean cell volume (MCV), the apparent utilization of dry matter (DM) and metabolizable energy (ME), villus height (VH) and villus height-to-crypt depth ratio (V:C) (P < 0.05). Fe-Gly also significantly up-regulated barrier-related genes including zonula occludens-1 (ZO-1), zonula occludens-2 (ZO-2), mucin 2 (MUC2) and lysozyme (LYZ) (P < 0.05), and down-regulated the mRNA expression of claudin-2 (CLDN2) and occludin (OCLN) in the jejunum (P < 0.05). The 16S rRNA sequence analysis indicated that the diet with Fe-Gly had a higher relative abundance of Intestinimonas and Romboutsia (P < 0.05), which have an ability to produce short chain fatty acids (SCFAs), especially butyric acid. It also decreased the relative abundance of pathobiont, including Megamonas, Eubacterium_coprostanoligenes_group and Plebeius (P < 0.05). Additionally, diets supplemented with 120 mg/kg Fe-Gly significantly increased the apparent utilization of DM and ME (P < 0.05) and decreased the relative abundance of Megamonas_unclassified and Bacteroides_unclassified compared with those fed 120 mg/kg FeSO4 (P < 0.05). These results revealed that diets supplemented with Fe-Gly exerted a potent beneficial effect on physical, chemical, immune and microbial barriers, thereby improving the integrity of the intestinal structure, promoting the digestion and absorption of nutrients to a certain extent, and ultimately elevating the growth performance of ducks.

Identification of a novel mutation in CYBB gene in a Chinese neonate with X-linked chronic granulomatous disease: A case report.

RATIONALE: X-linked chronic granulomatous disease (X-CGD) is an X-linked recessive disorder of the Nicotinamide adenine dinucleotide phosphate oxidase system that can cause primary immunodeficiency. Mutations in the CYBB gene located in Xp21.1 were accounting for X-CGD disease. More than 600 mutations have been identified as the cause of X-CGD in various populations worldwide. PATIENT CONCERNS AND DIAGNOSIS: In this study, the proband suffered from elevated white blood cells (WBC, 23.65 × 109/L), mainly in neutral (16.4 × 109/L). The neutrophil oxidative index of the patient was 2.13, which was extremely low, whereas his mother was 69.0 (Ref >100). Next, next-generation sequencing of the primary immunodeficiency diseases -related gene panel was performed. One novel mutation was identified in the CYBB gene in the CGD case: c.55C>G in exon 2. The mutation was verified by Sanger sequencing. The mother of the patient was heterozygous for the c.55C>G mutation, and the father was normal. These mutations were not present in the 100 unrelated normal controls. INTERVENTIONS AND OUTCOMES: The patient died from severe and uncontrollable pulmonary infection at 3 months of age. LESSONS: The identification of these mutations in this study further expands the spectrum of known CYBB gene mutations and contributes to the genetic counseling and prenatal molecular diagnosis of X-CGD.

Evaluation of effect of empirical attack-preventive immunotherapies in neuromyelitis optica spectrum disorders: An update systematic review and meta -analysis.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system, which mainly involves the optic nerve and spinal cord. Frequent relapse can accumulate the degree of disability. At present, the main treatment options are immunosuppressants and blood purification. The first-line immunosuppressants for NMOSD are mainly rituximab (RTX), mycophenolate mofetil (MMF) and azathioprine (AZA). Therefore, we designed this systematic review and meta-analysis to evaluate the safety and effect of the above three drugs in the treatment of NMOSD patients. METHODS: The following Medical Subject Heading (MeSH) and related entry terms are used to search English literature in PubMed, MEDLINE and CENTRAL databases, respectively. MeSH include: Neuromyelitis optic and Rituximab or Azathioprine or Mycophenolate Mofetil; entry terms include: NMO Spectrum Disorder, NMO Spectrum Disorders, Neuromyelitis Optica (NMO) Spectrum Disorder, Neuromyelitis Optica Spectrum Disorders, Devic Neuromyelitis Optica, Neuromyelitis Optica, Devic, Devic's Disease, Devic Syndrome, Devic's Neuromyelitis Optica, Neuromyelitis Optica (NMO) Spectrum Disorders, CD20 Antibody, Rituximab CD20 Antibody, Mabthera, IDEC-C2B8 Antibody, GP2013, Rituxan, Mycophenolate Mofetil, Mofetil, Mycophenolate, Mycophenolic Acid, Morpholinoethyl Ester, Cellcept, Mycophenolate Sodium, Myfortic, Mycophenolate Mofetil Hydrochloride, Mofetil Hydrochloride, Mycophenolate, RS 61443, RS-61443, RS61443, azathioprine sodium, azathioprine sulfate (note: literature retrieval operators "AND" "OR" "NOT" are used to link MeSH with Entry Terms.) The literature search found a total of 3058 articles about rituximab, mycophenolate mofetil and azathioprine in the treatment of NMOSD, 63 of which were included in this study after a series of screening. RESULTS: 930,933,732 patients with NMOSD were enrolled, who had been treated with MMF, AZA and RTX, respectively. The pooled standardized mean difference (SMD) of EDSS before and after RTX treated was -0.58 (95%CI: -0.72, -0.44) (I2 = 0%, p = 0.477), before and after MMF treated was -0.47 (95%CI: -0.73, -0.21) (I2 = 85.6%, p<0.001), before and after AZA treated was -0.41 (95%CI: -0.60, -0.23) (I2 = 65.4%, p<0.001). there was no significant difference in the effect of the three drugs on reducing EDSS scores (RTX vs MMF, p = 0.522; RTX vs AZA, p = 0.214; MMF vs AZA, p = 0.732). The pooled standardized mean difference (SMD) of ARR before and after RTX treated was -1.45 (95%CI: -1.72, -1.18) (I2 = 72.4%, p<0.001), before and after MMF treated was -1.14 (95%CI: -1.31, -0.97) (I2 = 54.5%, p<0.001), before and after AZA treated was -1.11 (95%CI: -1.39, -0.83) (I2 = 83.4%, p<0.001). RTX significantly reduced ARR compared with the other two drugs (RTX vs MMF, p = 0.039; RTX vs AZA, p = 0.049; MMF vs AZA, p = 0.436). CONCLUSION: The results of this systematic review and meta-analysis showed that the treatment of NMOSD patients with RTX, MMF and AZA is associated with decreased number of relapses and disability improvement as well, and there was no significant difference in the effect of the three drugs on reducing EDSS scores, but RTX significantly reduced ARR compared with the other two drugs.

Virtual Reality-Based Analysis of Pressure Ulcer Care Information Related to Medical Equipment for the Prevention of Pressure Ulcer Skin Foam Dressings in the Elderly.

As the standard of life has increased with the advancement of the time, there has been an increasing stress on healthcare with the aging diet, and pressure sores occur in elderly hospitalized subjects. Of course, the emergence of related medical devices, especially auxiliary foam dressings, is constantly improving. Pressure ulcers are extremely harmful to the elderly. The use of virtual reality technology to simulate the treatment of foam excipients is to test the role of medical devices in virtual reality. In particular, the use of foam dressings in the management of pressure deposits is the most relevant study for this paper, which reviews the relevant literature and conducts a thematic study on patients in a specific urban hospital. The relevant materials were designed, the experiments were designed, and the relevant research data were obtained. Studies show that virtual reality-based preventive medical devices can improve the efficiency of pressure ulcer treatment in hospitals by about 12%. Pressure ulcers have different incidences among people of different ages. The probability is much higher than that of adolescents. Foam dressing is very effective in preventing pressure ulcers. The probability of pressure ulcers after using foam dressing is about 35% lower than that when it is not used.

Transmission of a Novel Imprinting Center Deletion Associated With Prader-Willi Syndrome Through Three Generations of a Chinese Family: Case Presentation, Differential Diagnosis, and a Lesson Worth Thinking About.

Prader-Willi syndrome (PWS) is a complex genetic syndrome caused by the loss of function of genes in 15q11-q13 that are subject to regulation by genomic imprinting and expressed from the paternal allele only. The main clinical features of PWS patients are hypotonia during the neonatal and infantile stages, accompanied by delayed neuropsychomotor development, hyperphagia, obesity, hypogonadism, short stature, small hands and feet, mental disabilities, and behavioral problems. However, PWS has a clinical overlap with other disorders, especially those with other gene variations or chromosomal imbalances but sharing part of the similar clinical manifestations with PWS, which are sometimes referred to as Prader-Willi syndrome-like (PWS-like) disorders. Furthermore, it is worth mentioning that significant obesity as a consequence of hyperphagia in PWS usually develops between the ages of 1 and 6 years, which makes early diagnosis difficult. Thus, PWS is often not clinically recognized in infants and, on the other hand, may be wrongly suspected in obese and intellectually disabled patients. Therefore, an accurate investigation is necessary to differentiate classical PWS from PWS-like phenotypes, which is imperative for further treatment. For PWS, it is usually sporadic, and very rare family history and affected siblings have been described. Here, we report the clinical and molecular findings in a three-generation family with a novel 550-kb microdeletion affecting the chromosome 15 imprinting center (IC). Overall, the present study finds that the symptoms of our patient are somewhat different from those of typical PWS cases diagnosed and given treatment in our hospital. The familial occurrence and clinical features were challenging to our diagnostic strategy. The microdeletion included a region within the complex small nuclear ribonucleoprotein polypeptide protein N (SNRPN) gene locus encompassing the PWS IC and was identified by using a variety of techniques. Haplotype studies suggest that the IC microdeletion was vertically transmitted from an unaffected paternal grandmother to an unaffected father and then caused PWS in two sibling grandchildren when the IC microdeletion was inherited paternally. Based on the results of our study, preimplantation genetic diagnosis (PGD) was applied successfully to exclude imprinting deficiency in preimplantation embryos before transfer into the mother's uterus. Our study may be especially instructive regarding accurate diagnosis, differential diagnosis, genetic counseling, and PGD for familial PWS patients.

Internal hernia beneath superior vesical artery after pelvic lymphadenectomy for cervical cancer: a case report and literature review.

BACKGROUND: The common complications of radical hysterectomy and pelvic lymphadenectomy usually include wound infection, hemorrhage or hematomas, lymphocele, uretheral injury, ileus and incisional hernias. However, internal hernia secondary to the orifice associated with the uncovered vessels after pelvic lymphadenectomy is very rare. CASE PRESENTATION: We report a case of internal hernia with intestinal perforation beneath the superior vesical artery that occurred one month after laparoscopic pelvic lymphadenectomy for cervical cancer. A partial ileum resection was performed and the right superior vesical artery was transected to prevent recurrence of the internal hernia. CONCLUSIONS: Retroperitonealization after the pelvic lymphadenectomy should be considered in patients with tortuous, elongated arteries which could be causal lesions of an internal hernia.

Up-regulation of long noncoding RNA LINC00858 is associated with poor prognosis in gastric cancer.

BACKGROUND: The present study aimed to investigated the expression pattern of long noncoding RNA LINC00858 (LINC00858) in gastric cancer (GC) patients and its feasibility as a new prognostic biomarker. METHODS: We examined LINC00858 expression in GC tissues and matched normal tissues from 189 patients using a quantitative reverse transcription-polymerase chain reaction. The correlations of LINC00858 levels in GC patients with clinicopathologic features were analyzed using a chi-squared test. The influence of LINC00858 on the overall survival rate of GC patients was precisely calculated using Kaplan-Meier methods (log rank tests). Multivariate Cox regression assays were carried out for the identification of the independent risk factors for GC. RESULTS: We observed that LINC00858 was distinctly up-regulated in GC tissues compared to adjacent non-tumor specimens (p < 0.01). Higher expression of LINC00858 in GC was found to be associated with TNM stage (p = 0.003) and lymphatic metastasis (p = 0.007). Using Kaplan-Meier assays, we found that patients with high expression levels of LINC00858 had a distinctly poor overall survival and disease-free survival compared to those with low expression levels of LINC00858 (p = 0.0102). Multivariate analyses confirmed that LINC00858 (p < 0.05) was an independent prognosis factor for GC patients. CONCLUSIONS: The data obtained in our study indicate that LINC00858 may be used as a novel prognostic indicator in GC patients.

Esculetin enhances the inhibitory effect of 5-Fluorouracil on the proliferation, migration and epithelial-mesenchymal transition of colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the most common malignant disease worldwide and thus new therapeutic approaches are needed. 5-Fluorouracil (5-FU) remains the most widely used agent to treat colorectal cancer (CRC). However, its clinical efficacy is currently limited by the development of drug resistance. Esculetin (EST), a coumarin, was found to have anti-proliferative and anti-migration activity in cancer. OBJECTIVE: This research aims to evaluated the influence and possible mechanism of EST on the proliferation, migration and epithelial-mesenchymal transition of CRC cell lines. MATERIALS AND METHODS: Human CRC cell lines HT-29, SW480, HCT-116, and Caco-2 were treated with various concentrations of EST (0.2, 2, 20, 200, 2000 µg/ml) or 5-FU (0.1, 1, 10, 100, 1000 µg/ml) for 48 h, and cell viability was determined by the MTT and CCK-8 assay. The motility of HCT-116 cells was detected by scratch assay. Western blot was applied to detect the protein expression. Besides, levels of Wnt3a and VEGF in HCT-116 cell culture medium supernatant were analyzed by ELISA. The anti-tumor effect was detected with HCT-116 subcutaneous tumor bearing tumor model by monitoring the tumor vomume in vivo. Finally, the tumoral expression of VEGF was measured by immunohistochemistry, and the expression of Ki67, PCNA, ß-catenin, c-Myc, Cyclin D1, MMP2 and MMP7 was measured by Western blot analysis. RESULTS: EST inhibited HCT-116 cell proliferation in a dose-dependent manner. Western blot analysis revealed that EST decreased the expression of Ki67, PCNA, N-cadherin, E-cadherin, vimentin, fibronectin, ß-catenin, c-Myc, Cyclin D1, MMP2 and MMP7. Furthermore, EST reduced the release of Wnt3a and VEGF into HCT-116 cells culture medium. After EST treatment, the tumor volume was significant smaller than that of the control group, and the tumoral levels of VEGF were decreased. Moreover, western blot analysis indicated that the expression of Ki67, PCNA, ß-catenin, c-Myc, Cyclin D1, MMP2 and MMP7 were also significantly decreased after treated with EST. In addition, in vitro and in vivo anti-tumor results demonstrated that EST combined with 5-FU could increase the inhibitory effect of 5-FU on HCT-116 cells proliferation, migration and epithelial-mesenchymal transition. CONCLUSIONS: EST enhances the inhibitory effect of 5-FU on the proliferation, migration and epithelial-mesenchymal transition of CRC.

An updated association between TNF-α -238G/A polymorphism and gastric cancer susceptibility in East Asians.

Polymorphisms in the tumor necrosis factor α (TNF-α) gene are emerging as key determinants of gastric diseases. The TNF-α-238G/A single-nucleotide polymorphism (SNP) is the most extensively studied. However, this association is inconsistent amongst different populations. We therefore conducted an updated meta-analysis to obtain a more precise estimate of the association of TNF-α-238G/A polymorphism with gastric cancer (GC) risk. A comprehensive search of PubMed, Embase, Chinese (CNKI and WanFang) databases was performed to identify relevant studies through 5 May 2018. Odds ratio (OR) and 95% confidence interval (CI) were used to assess the strength of the association. Fourteen studies were included in our meta-analysis involving 2999 cases and 4685 controls. There was no significant association between TNF-α-238G/A polymorphism and GC risk in the overall populations. In the subgroup analysis, we found that TNF-α-238G/A polymorphism was associated with the increased risk of GC amongst Asians, especially in Chinese, but not in Caucasians. Subgroup analysis by genotyping methods revealed increased risk for other methods. In conclusion, our present meta-analysis shows that TNF-α-238G/A polymorphism is associated with the risk of GC in East Asian individuals.

Discovery, cocrystallization and biological evaluation of novel piperidine derivatives as high affinity Ls-AChBP ligands possessing α7 nAChR activities.

A series of novel pyridine-substituted piperidine derivatives were discovered as low nanomolar Ls-AChBP ligands with α7 nAChR partial agonism or antagonism activities. A high-resolution antagonist-bound Ls-AChBP complex was successfully resolved with a classic Loop C opening phenomenon and unique sulfur-π interactions which deviated from our previous docking mode to a large extent. With the knowledge of the co-complex, 27 novel piperidine derivatives were designed and synthesized. The structure-activity relationships (SARs) of the aromatic and pyridine regions were well established and binding modes were illustrated with the help of molecular docking which indicated that interactions with Trp 143 and the "water bridge" are essential for the high binding affinities. Halogen bonding as well as the space around 5'- or 6'- position of the pyridine ring was also proposed to influence the binding conformation of the compounds. Notably, two enantiomers of compound 2 showed opposite functions toward α7 nAChR and compound (S)-2 showed sub-nanomolar affinity (Ki = 0.86 nM) on Ls-AChBP and partial agonism (pEC50 = 4.69 ±â€¯0.11,Emax = 36.1%) on α7 nAChR with reasonable pharmacokinetics (PK) properties and fine ability of blood-brain-barrier (BBB) penetration. This study provided promising hits to develop candidates targeting nAChR-related CNS diseases.

Regioselective Access to 3-Aryl-1-aminoisoquinolines via Nickel(I)-Catalyzed C-C and C-N Cascade Coupling Reactions from the Substituted 2-(Cyanomethyl)benzonitriles.

A novel and regioselective Ni(I) catalyzed C-C and C-N cascade coupling reactions has been developed. The cascade furnishes atom-economic access to 40 3-aryl-1-aminoisoquinolines. The regioselectivity of C(sp3)-cyano group over C(sp2)-cyano group was revealed and supported by mechanism studies as well as the preliminary density functional theory (DFT) calculations.

Circulating SH2B1 is associated with an increased risk of gastric cancer.

Gastric cancer (GC) is one of the most common types of cancer in humans and the second leading cause of cancer-associated mortality worldwide. Identifying novel risk factors will facilitate the development of therapeutic strategies to prevent and treat GC. Increased expression of the Src homology 2 B adaptor protein 1 (SH2B1) may stimulate the malignant progression of lung cancer, esophageal cancer and neuroblastoma. However, its function in GC has not yet been investigated. To identify whether increased serum SH2B1 is a risk factor for GC, the present study performed a nested case-control study of patients within the Chinese cohort study. Levels of serum SH2B1 were measured in 563 patients diagnosed with GC during the follow-up period and in 1,126 matched healthy controls. The results demonstrated that high levels of serum SH2B1 were associated with an increased GC risk (odds ratio, 3.23; 95% confidence interval, 2.45-5.65). When analyses were stratified further by sex, age and smoking, an association between increased levels of SH2B1 and GC was identified in males but not in females. Furthermore, the association between SH2B1 levels and GC was more evident in younger than in older participants, and statistically significant in current smokers but not in nonsmokers. These results were not altered following the exclusion of outliers. Furthermore, it was demonstrated that overexpression of SH2B1 contributes to the malignant transformation of normal gastric epithelial cells. Thus, the present study demonstrated that elevated serum SH2B1 levels may increase the risk of GC.

Discovery of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amines as potent, selective and orally bioavailable LRRK2 inhibitors.

Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson's disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100 mg/kg) and mice (45 mg/kg) following oral administration.

Microwave-assisted synthesis of hydroxyl-containing isoquinolines by metal-free radical cyclization of vinyl isocyanides with alcohols.

A convenient microwave-assisted protocol for the synthesis of hydroxyl-containing isoquinolines from a metal-free radical cyclization reaction of vinyl isonitriles with alcohols was developed with moderate-to-excellent yields. Vinyl isonitriles are coupled with alkyl radicals through direct catalytic functionalization of the α sp3 C-H bond of alcohols. The methodology demonstrates a broad substrate scope, shows excellent functional group tolerance, is highly atom-economical and highly efficient, thus enabling the preparation of diverse potentially valuable hydroxyl-containing isoquinolines.