The receptor for the luteinizing hormone (LH-R) is aberrantly over expressed in cancers of the reproductive system. To uncover whether LH-R over expression has a causative role in cancer, we ...generated a transgenic (TG) mouse which overexpresses the human LH-R (hLH-R) in the female reproductive tract, under the control of the oviduct-specific glycoprotein (OGP) mouse promoter (mogp-1). The transgene was highly expressed in the uterus, ovary and liver, but only in the uterus morphological and molecular alterations (increased proliferation and trans-differentiation in the endometrial layer) were detected. A transcriptomic analysis on the uteri of young TG mice showed an up regulation of genes involved in cell cycle control and a down regulation of genes related to the immune system and the metabolism of xenobiotics. Aged TG females developed tumor masses in the uteri, which resembled an Endometrial Cancer (EC). Microarray and immunohistochemistry data indicated the deregulation of signaling pathways which are known to be altered in human ECs. The analysis of a cohort of 126 human ECs showed that LH-R overexpression is associated with early-stage tumors. Overall, our data led support to conclude that LH-R overexpression may directly contribute to trigger the neoplastic transformation of the endometrium.
The salivary α-amylase locus (AMY1) is located in a highly polymorphic multi allelic copy number variable chromosomal region. A recent report identified an association between AMY1 copy numbers and ...BMI in common obesity. The present study investigated the relationship between AMY1 copy number, BMI and serum amylase in childhood-onset obesity.
Sixty-one subjects with a history of childhood-onset obesity (mean age 19.1 years, 54% males) and 71 matched controls (19.8 yrs, 45% males) were included. All anthropometric measures were greater in the obese; their mean BMI was 40 kg/m2 (range 25-62 kg/m2) compared with 23 kg/m2 in the controls (15-32 kg/m2).
Mean AMY1 copy numbers did not differ between the obese and control subjects, but gender differences were observed; obese men showed the highest and obese women the lowest number of AMY1 copies (p=0.045). Further, only in affected females, AMY1 copy number correlated significantly with whole body fat percent (r=-0.512, p=0.013) and BMI (r=-0.416, p=0.025). Finally, a clear linear association between AMY1 copy number and serum salivary amylase was observed in all subgroups but again differences existed between obese males and females.
In conclusion, our findings suggest that AMY1 copy number differences play a role in childhood-onset obesity but the effect differs between males and females. Further studies in larger cohorts are needed to confirm these observations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Context
Only a few genetic causes for childhood obesity have been identified to date. Copy number variants (CNVs) are known to contribute to obesity, both syndromic (15q11.2 deletions, ...Prader-Willi syndrome) and nonsyndromic (16p11.2 deletions) obesity.
Objective
To study the contribution of CNVs to early-onset obesity and evaluate the expression of candidate genes in subcutaneous adipose tissue.
Design and Setting
A case-control study in a tertiary academic center.
Participants
CNV analysis was performed on 90 subjects with early-onset obesity and 67 normal-weight controls. Subcutaneous adipose tissue from body mass index-discordant siblings was used for the gene expression analyses.
Main Outcome Measures
We used custom high-density array comparative genomic hybridization with exon resolution in 1989 genes, including all known obesity loci. The expression of candidate genes was assessed using microarray analysis of messenger RNA from subcutaneous adipose tissue.
Results
We identified rare CNVs in 17 subjects (19%) with obesity and 2 controls (3%). In three cases (3%), the identified variant involved a known syndromic lesion (22q11.21 duplication, 1q21.1 deletion, and 16p11.2 deletion, respectively), although the others were not known. Seven CNVs in 10 families were inherited and segregated with obesity. Expression analysis of 37 candidate genes showed discordant expression for 10 genes (PCM1, EFEMP1, MAMLD1, ACP6, BAZ2B, SORBS1, KLF15, MACROD2, ATR, and MBD5).
Conclusions
Rare CNVs contribute possibly pathogenic alleles to a substantial fraction of children with early-onset obesity. The involved genes might provide insights into pathogenic mechanisms and involved cellular pathways. These findings highlight the importance of CNV screening in children with early-onset obesity.
We studied genetic copy number variants in subjects with childhood-onset obesity and normal-weight controls. Rare variants were significantly more common in affected individuals than in controls.
Congenital malformations affecting the neural tube can present as isolated malformations or occur in association with other developmental abnormalities and syndromes. Using high‐resolution copy ...number screening in 66 fetuses with neural tube defects, we identified six fetuses with likely pathogenic mutations, three aneuploidies (one trisomy 13 and two trisomy 18) and three deletions previously reported in NTDs (one 22q11.2 deletion and two 1p36 deletions) corresponding to 9% of the cohort. In addition, we identified five rare deletions and two duplications of uncertain significance including a rare intragenic heterozygous in‐frame WDR63 deletion in a fetus with occipital encephalocele. Whole genome sequencing verified the deletion and excluded known pathogenic variants. The deletion spans exons 14–17 resulting in the expression of a protein missing the third and fourth WD‐repeat domains. These findings were supported by CRISPR/Cas9‐mediated somatic deletions in zebrafish. Injection of two different sgRNA‐pairs targeting relevant intronic regions resulted in a deletion mimicking the human deletion and a concomitant increase of abnormal embryos with body and brain malformations (41%, n = 161 and 62%, n = 224, respectively), including a sac‐like brain protrusion (7% and 9%, P < 0.01). Similar results were seen with overexpression of RNA encoding the deleted variant in zebrafish (total abnormal; 46%, n = 255, P < 0.001) compared with the overexpression of an equivalent amount of wild‐type RNA (total abnormal; 3%, n = 177). We predict the in‐frame WDR63 deletion to result in a dominant negative or gain‐of‐function form of WDR63. These are the first findings supporting a role for WDR63 in encephalocele formation.
High resolution copy number screening of 66 fetuses with neural tube defects identified six fetuses with likely pathogenic variants (three aneuploidies and three previously reported deletions). We also identified five rare deletions and two duplications of uncertain significance, including a rare intragenic heterozygous in‐frame WDR63 deletion in a fetus with occipital encephalocele. The deletion spans exons 14‐17, resulting in a protein missing the third and fourth WD‐repeat domains. Functional studies in zebrafish support a role for the identified WDR63 variant in encephalocele formation.
Patients with metastatic colorectal cancer (mCRC) are routinely screened for either K- and N-RAS to select the appropriate treatment. The present study aimed to evaluate the concordance between K- ...and NRAS status in the tissue (either primary tumor or metastasis) and the plasma of patients with mCRC and to identify the associations between K- and NRAS mutations in ctDNA and the clinicopathological parameters. Samples from a total of 31 patients with mCRC with measurable disease according to the Response Evaluation Criteria in Solid Tumors were analyzed. For all patients, K- and NRAS status was determined in the tissue by matrix-assisted laser desorption/ionization time of flight mass spectrometry. For the detection of RAS mutations in cell-free tumor DNA also defined as circulating tumor DNA (ctDNA), the OncoBEAMR RAS CRC kit (Sysmex Inostics) was used. A total of 6/31 tissue samples expressed wild-type KRAS, whereas 25/31 presented mutations. In addition, 7/31 plasma samples expressed wild-type KRAS, mutations were detected in 22/31 patients, and for 2/31 patients, the test did not provide a conclusive result. A total of 24/31 patients expressed wild-type NRAS, 6/31 had mutations and 1/21 was not informative. For the KRAS mutational status, a moderate concordance (agreement, 85.18%; Cohen's k, 0.513) between the tissue and plasma analysis was observed; for NRAS, a fair agreement (agreement, 83.33%; Cohen's k, 0.242) was obtained. In conclusion, both tissue and plasma analyses should be performed for the management of patients with mCRC. To better exploit the beads, emulsions, amplification, magnetics (BEAMing) technique in the clinical setting, studies aimed at determining the RAS status to monitor therapy and during follow-up are warranted. Key words: metastatic colorectal cancer, KRAS, NRAS, mass spectrometry, beads, emulsions amplification, magnetics
Interleukins (ILs) are involved in the occurrence and development of numerous types of cancer, and serve a critical role in the development of effective cancer therapeutics. The aim of the present ...study was to investigate the effect of IL-27 on chemotherapy resistance in lung cancer cells, and analyze its potential molecular mechanism in lung cancer tissues. Western blot analysis and reverse transcription-quantitative polymerase chain reaction were performed to examine the RNA and protein expression levels of IL-27. A Cell Counting Kit-8 assay was performed to evaluate the proliferation rates of the lung cancer line A549. Flow cytometry was subsequently applied to determine the rate of apoptosis in A549 cells. The data obtained revealed that the expression of IL-27 with cisplatin, significantly suppressed the proliferation and apoptosis of A549 cells compared with that in the cisplatin treatment group alone. The expression of Akt and apoptosis factors such as Caspase-3 and Bcl-2/Bax also ascertained that upregulated IL-27 inhibited the development of cancer and increased apoptosis in the A549 cells. Therefore, IL-27 may represent a potential target for antitumor therapy, especially when considering the clinical challenges presented by the development of chemoresistance in tumors. These findings suggest that IL-27 is a promising biomarker and represents a novel treatment strategy for patients with lung cancer.
Background The salivary alpha -amylase locus (AMY1) is located in a highly polymorphic multi allelic copy number variable chromosomal region. A recent report identified an association between AMY1 ...copy numbers and BMI in common obesity. The present study investigated the relationship between AMY1 copy number, BMI and serum amylase in childhood-onset obesity. Patients Sixty-one subjects with a history of childhood-onset obesity (mean age 19.1 years, 54% males) and 71 matched controls (19.8 yrs, 45% males) were included. All anthropometric measures were greater in the obese; their mean BMI was 40 kg/m2 (range 25-62 kg/m2) compared with 23 kg/m2 in the controls (15-32 kg/m2). Results Mean AMY1 copy numbers did not differ between the obese and control subjects, but gender differences were observed; obese men showed the highest and obese women the lowest number of AMY1 copies (p=0.045). Further, only in affected females, AMY1 copy number correlated significantly with whole body fat percent (r=-0.512, p=0.013) and BMI (r=-0.416, p=0.025). Finally, a clear linear association between AMY1 copy number and serum salivary amylase was observed in all subgroups but again differences existed between obese males and females. Conclusions In conclusion, our findings suggest that AMY1 copy number differences play a role in childhood-onset obesity but the effect differs between males and females. Further studies in larger cohorts are needed to confirm these observations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Characterizing readmissions from orthopedic surgical site infections.
An integrative review of literature in the LILACS, IBECS, MEDLINE, Cochrane, SciELO and PUBMED databases, using the descriptors ...Patient readmission, Wound infection, Cross infection, Orthopedic procedures, Orthopedics.
78 studies were identified and 10 publications were selected. Surgical site infections are the most common cause of unplanned orthopedic readmissions, representing long periods of hospitalization, new surgical procedures and high costs, and greater possibility of subsequent hospitalizations. Most significant predictors have indicated average length of hospitalization, need for intensive care, emergency status at admission, risk of death, age > 65 years, males and higher body mass index.
Readmission rates have increasingly become measures of quality and concerns about costs. New studies could involve issues related to indirect costs, specifically social and psychological costs.
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