Is the presence of Merkel cell polyomavirus and human papillomavirus DNA in keratinocyte cancers and precancers associated with HIV status? A case-control study.

The epidemiology and potential pathogenic roles of human papillomavirus (HPV) and Merkel cell polyomavirus (MCV) in keratinocyte cancers (KCs) arising in people living with HIV (PLWH) compared with HIV-negative individuals are poorly understood. These issues were investigated by a case-control study in which the presence of MCV and HPV DNA was identified by polymerase chain reaction in microdissected formalin-fixed paraffin-embedded tissue from PLWH and HIV-negative individuals. The samples comprised 190 cutaneous and genital KCs/precancers (actinic keratoses, n = 43; cutaneous squamous cell carcinoma (cSCC) in situ, n = 24; basal cell carcinoma, n = 78; cSCC, n = 34; penile carcinoma in situ, n = 9; penile SCC, n = 2 from 104 individuals (PLWH, n = 51; HIV-negative, n = 53). Almost one-quarter of samples were positive for MCV: this was not significantly associated with either HIV status (P = 0.06) nor lesion type. Overall, 36% (16/44) of MCV-positive lesions were coinfected with HPV; this was also not associated with HIV status. These findings indicate that if these viruses do contribute to the pathogenesis of KCs, it is likely to be independent of HIV status.

Genome-wide association analyses define pathogenic signaling pathways and prioritize drug targets for IgA nephropathy.

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum IgA levels. High polygenic score for IgAN was associated with earlier onset of kidney failure. In a comprehensive functional annotation analysis of candidate causal genes, we observed convergence of biological candidates on a common set of inflammatory signaling pathways and cytokine ligand-receptor pairs, prioritizing potential new drug targets.

Update of a prognostic survival model in head and neck squamous cell carcinoma patients treated with immune checkpoint inhibitors using an expansion cohort.

BACKGROUND: Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. METHODS: A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. RESULTS: 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. CONCLUSIONS: Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective.

The genomics and epigenetics of olfactory neuroblastoma: A systematic review.

BACKGROUND: Olfactory neuroblastoma (ONB) or esthesioneuroblastoma (ENB) is a rare malignancy of the nasal cavity believed to arise from the olfactory epithelium. The goal of this study was to systematically review the genomics, epigenetics, and cytogenetics of ONB and to understand the potential clinical implications of these studies. METHODS: A systematic literature review was performed for articles published before May 2020 using Cochrane, Embase, Pubmed, and Scopus databases. Inclusion criteria included genomics, cytogenetics, and epigenetics studies on ONB. Exclusion criteria included studies not in English or systematic reviews. Articles and abstracts were reviewed by two independent reviewers to reduce bias during article selection and synthesis of results. Of the 36 studies included in this review, 24 were research articles and 12 were abstracts. RESULTS: Although recurrent mutations among ONB tumors are uncommon, alterations in TP53, DMD, PIK3CA, NF1, CDKN2A, CDKN2C, CTNNB1, EGFR, APC, cKIT, cMET, PDGFRA, CDH1, FH, SMAD4, FGFR3 and IDH2 genes have been reported in several recent studies. In addition, cytogenetic studies revealed that the landscape of chromosomal aberrations varies widely amongst ONB tumors. CONCLUSIONS: The rare character of ONB has limited the sample size available for cytogenetic, genomic, and epigenetic studies and contributes to the limitations of this systematic review. Comprehensive genomic and epigenomic studies with larger cohorts are warranted to validate the initial reports summarized in this review and to identify potential therapeutic targets for ONB.

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis.

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk.

A Unique Panel of Patient-Derived Cutaneous Squamous Cell Carcinoma Cell Lines Provides a Preclinical Pathway for Therapeutic Testing.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) incidence continues to rise with increasing morbidity and mortality, with limited treatment options for advanced disease. Future improvements in targeted therapy will rely on advances in genomic/transcriptomic understanding and the use of model systems for basic research. We describe here the panel of 16 primary and metastatic cSCC cell lines developed and characterised over the past three decades in our laboratory in order to provide such a resource for future preclinical research and drug screening. METHODS: Primary keratinocytes were isolated from cSCC tumours and metastases, and cell lines were established. These were characterised using short tandem repeat (STR) profiling and genotyped by whole exome sequencing. Multiple in vitro assays were performed to document their morphology, growth characteristics, migration and invasion characteristics, and in vivo xenograft growth. RESULTS: STR profiles of the cSCC lines allow the confirmation of their unique identity. Phylogenetic trees derived from exome sequence analysis of the matched primary and metastatic lines provide insight into the genetic basis of disease progression. The results of in vivo and in vitro analyses allow researchers to select suitable cell lines for specific experimentation. CONCLUSIONS: There are few well-characterised cSCC lines available for widespread preclinical experimentation and drug screening. The described cSCC cell line panel provides a critical tool for in vitro and in vivo experimentation.

miR-4516 predicts poor prognosis and functions as a novel oncogene via targeting PTPN14 in human glioblastoma.

Glioblastomas (GBMs) are the most aggressive primary brain tumors, with an average survival of less than 15 months. Therefore, there is a critical need to develop novel therapeutic strategies for GBM. This study aimed to assess the prognostic value of miR-4516 and investigate its oncogenic functions and the underlying cellular and molecular mechanisms in GBM. To determine the correlation between miR-4516 expression and overall survival of patients with GBM, total RNAs were isolated from 268 FFPE tumor samples, miR expression was assayed (simultaneously) using the nCounter human miRNA v3a assay followed by univariable and multivariable survival analyses. Further, in vitro and in vivo studies were conducted to define the role of miR-4516 in GBM tumorigenesis and the underlying molecular mechanisms. Upon multivariable analysis, miR-4516 was correlated with poor prognosis in GBM patients (HR = 1.49, 95%CI: 1.12-1.99, P = 0.01). Interestingly, the significance of miR-4516 was retained including MGMT methylation status. Overexpression of miR-4516 significantly enhanced cell proliferation and invasion of GBM cells both in vitro and in vivo. While conducting downstream targeting studies, we found that the tumor-promoting function of miR-4516, in part, was mediated by direct targeting of PTPN14 (protein tyrosine phosphatase, non-receptor type 14) which, in turn, regulated the Hippo pathway in GBM. Taken together, our data suggest that miR-4516 represents an independent negative prognostic factor in GBM patients and acts as a novel oncogene in GBM, which regulates the PTPN14/Hippo pathway. Thus, this newly identified miR-4516 may serve as a new potential therapeutic target for GBM treatment.

AJAP1 expression modulates glioma cell motility and correlates with tumor growth and survival.

Glioblastoma multiforme (GBM) is one of the most common primary malignant brain tumors. Unraveling the molecular and genetic complexity that determines GBM's pronounced migratory property could provide new options for therapeutic targeting that may significantly complement current surgical and chemoradiation therapy and alter the current poor outcome. In this study, we establish stable AJAP1 overexpressing glioma cells in order to examine in vivo tumor growth. We examine AJAP1 localization by confocal microscopy and AJAP1's functional effect on migration and invasion across surfaces coated with laminin. Finally, analysis of AJAP1 expression in murine xenografts and GBM primary tumors revealed its association with tumor growth and survival. Stable overexpression of AJAP1 promotes adherence, decreases invasion of glioma cells through an extracellular-like matrix, and slows migration in the presence of laminin. These observations are reversed by gene knockdown using multiple siRNAs. Additionally, overexpression of AJAP1 decreases colony formation in glioma cells, and leads to smaller tumor growth with increased survival in glioma xenograft mice. Loss of AJAP1 protein expression predicts worse survival in GBM patients. AJAP1 overexpression decreases cell motility in the presence of laminin and decreases tumor growth in xenografts. Its loss of expression predicts worse survival in patients. This study extends our prior observations and implicates AJAP1 as a potential prognostic marker and a viable target for therapeutic intervention in GBM.

GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway.

Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10-11) and C1GALT1C1 (rs5910940, P = 2.7 x 10-8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer.

Fine Mapping Implicates a Deletion of CFHR1 and CFHR3 in Protection from IgA Nephropathy in Han Chinese.

An intronic variant at the complement factor H (CFH) gene on chromosome 1q32 (rs6677604) associates with risk of IgA nephropathy (IgAN), but the association signal has not been uniformly replicated in Han Chinese populations. We investigated whether the causal sequence variant resides in the CFH gene or the neighboring complement factor H-related 1 (CFHR1) gene and CFHR3, which harbor an 84-kb combined deletion (CFHR3,1Δ) in linkage disequilibrium with rs6677604. Imputation of 1000 Genomes Project data did not suggest new causal single-nucleotide variants within the CFH cluster. We next performed copy number analysis across the CFH locus in two independent Han Chinese case-control cohorts (combined n=3581). The CFHR3,1Δ and rs6677604-A alleles were rare (4.4% in patients and 7.1% in controls) and in strong linkage disequilibrium with each other (r2=0.95); of these alleles, CFHR3,1Δ associated more significantly with decreased risk of IgAN (odds ratio [OR], 0.56; 95% confidence interval [95% CI], 0.46 to 0.70; P=8.5 × 10-8 versus OR, 0.61; 95% CI, 0.50 to 0.75; P=1.6 × 10-6 for rs6677604-A). Moreover, CFHR3,1Δ explained all of the association signal at rs6677604 and remained significant after conditioning on rs6677604 genotype (P=0.01). Exploratory analyses of clinical and histopathologic parameters using the Oxford classification criteria revealed a suggestive association of CFHR3,1Δ with reduced tubulointerstitial injury (OR, 0.46; 95% CI, 0.25 to 0.79). These data indicate that dysregulated activity of the alternative complement pathway contributes to IgAN pathogenesis in both Asians and Europeans and implicate CFHR3,1Δ as the functional allele at this locus.

Genome-wide association study in mice identifies loci affecting liver-related phenotypes including Sel1l influencing serum bile acids.

UNLABELLED: Using publicly available data from inbred mouse strains, we conducted a genome-wide association study to identify loci that accounted for liver-related phenotypes between C57BL/6J and A/J mice fed a Paigen diet. We confirmed genome-wide significant associations for hepatic cholesterol (chromosome 10A2) and serum total bile acid concentration (chromosome 12E) and identified a new locus for liver inflammation (chromosome 7C). Analysis of consomic mice confirmed that chromosome 12 A/J alleles accounted for the variance in serum total bile acid concentrations and had pleiotropic effects on liver mass, serum cholesterol, and serum alanine aminotransferase activity. Using an affected-only haplotype analysis among strains, we refined the chromosome 12E signal to a 1.95 Mb linkage disequilibrium block containing only one gene, sel-1 suppressor of lin-12-like (Sel1l). RNA sequencing and immunoblotting demonstrated that the risk allele locally conferred reduced expression of SEL1L in liver and distantly down-regulated pathways associated with hepatocyte nuclear factor 1 homeobox A (Hnf1a) and hepatocyte nuclear factor 4A (Hnf4a), known modifiers of bile acid transporters and metabolic traits. Consistent with these data, knockdown of SEL1L in HepG2 cells resulted in reduced HNF1A and HNF4A and increased bile acids in culture media; it further captured multiple molecular signatures observed in consomic mouse livers with reduced SEL1L. Finally, dogs harboring a SEL1L mutation and Sel1l(+/-) mice fed a Paigen diet had significantly increased serum total bile acid concentrations, providing independent confirmation linking SEL1L to bile acid metabolism. CONCLUSION: Genetic analyses of inbred mouse strains identified loci affecting different liver-related traits and implicated Sel1l as a significant determinant of serum bile acid concentration. (Hepatology 2016;63:1943-1956).

Evaluation of disease activity in ankylosing spondylitis; diagnostic value of color Doppler ultrasonography.

INTRODUCTION: Spondyloarthropathies including ankylosing spondylitis (AS) require early diagnosis to prevent irreversible changes. Sacroiliitis is a common initial manifestation of AS and is frequently diagnosed by magnetic resonance imaging (MRI). The goal of our study was to assess color Doppler ultrasonography as a potential diagnostic tool in suspected sacroiliitis in comparison with MRI representing the gold standard. MATERIALS AND METHODS: Fifty-one consecutive patients with AS and sacroiliitis and 30 control subjects underwent contrast-enhanced MRI and high resolution color Doppler and duplex ultrasonography of both sacroiliac joints (SIJ) for the detection of vascularization and blood flow spectral Doppler waveform analysis. RESULTS: MRI demonstrated active disease in 27 and inactive disease in 24 patients. CDUS detected pulsatile monophasic wave spectral waveform flow in 22 patients with the active disease, and triphasic in 7 patients with inactive disease and in 8 control patients. The sensitivity, specificity, positive predictive value and negative predictive value for active sacroiliitis detection with CDUS were 82 % (95 % CI, 68-91 %), 92 % (95 % CI, 85-96 %), 91 % (95 % CI, 84-96 %), and 84 % (95 % CI, 70-92 %), respectively, for pulsatile monophasic wave spectral waveform Doppler sonography. MRI of SIJ was negative in all 30 (60 SIJ) control participants. CONCLUSIONS: Our results show that CDUS is a practical and useful tool in the diagnosis of active sacroiliitis.

Prevalence of depression and depressive symptoms in patients with systemic lupus erythematosus: Iranian experience.

Psychiatric disorders including depression represent clinical manifestation of systemic lupus erythematosus (SLE). Recognition of depression in SLE patients is of utmost importance since it is treatable and can be of fatal consequences if unrecognized. This study was conducted to determine the prevalence of depression and depressive symptoms in SLE patients in terms of age, gender, disease duration and severity, and duration of steroid treatment in SLE patients. Eighty-five SLE patients (77 women, 8 men) with verified SLE diagnosis completed Beck's depression inventory, a self-reported measure of depression. Clinical data on disease and treatment were obtained from patient files. In total, 60% of patients achieved scores indicating depression. The most common depressive symptoms in participants were fatigue and weakness (88.2%), irritability (82.3%), sadness (77.6%), and somatic preoccupation (76.4%), while the least common symptoms were weight loss (34.1%), low level of energy (28.2%), and suicide ideation (10.5%). There was a significant difference between the disease activity and the severity of depression (P = 0.0001). Our findings show higher prevalence of depression in our sample in comparison with previous studies, suggesting that the prevalence of depression varies across different populations. Severity of depression increases with more severe disease course.

Role of iron supplementation in promoting maternal and fetal outcome.

BACKGROUND: The data comparing daily versus intermittent iron supplementation during pregnancy remain controversial. This study was undertaken to compare the efficacy of daily versus two different intermittent iron supplementation regimes on hematologic markers and birth outcomes in nonanemic pregnant women. METHODS: Two hundred and ten women with singleton pregnancies, no known disease, and hemoglobin levels >11.0 g/dL were randomly assigned to one of three groups, ie, Group A consuming two iron supplementation tablets once weekly (100 mg iron per week, n = 70), Group B consuming one tablet twice weekly (100 mg iron per week, n = 70) and Group C, consuming one tablet daily (50 mg iron per day, n = 70). No additional micronutrients were supplied. Hemoglobin and serum ferritin levels were measured at 20, 28, and 38 weeks. Pregnancy and birth outcomes (pregnancy termination, method of delivery, birth weight, stillbirth) were analyzed. RESULTS: In total, 201 women completed the protocol. There was a significant difference in mean hemoglobin and ferritin levels in Group B at 38 weeks (P = 0.018 and P = 0.035, respectively) but this difference was not clinically significant (hemoglobin >12 g/dL, ferritin >19 µg/L). There was a significant increase in ferritin in Group C (P = 0.03) at 28 weeks. No significant difference was observed with respect to pregnancy or birth outcome across the groups. All regimens prevented the occurrence of hemoglobin <10.5 g/dL, but weekly supplementation was associated with development of a hemoglobin level <11.0 g/dL (risk ratio 0.044). CONCLUSION: Twice-weekly supplementation is as effective as daily supplementation, and may represent an acceptable compromise in iron supplementation regimens for nonanemic pregnant women.

Effect of Helicobacter pylori infection on pregnancy rates and early pregnancy loss after intracytoplasmic sperm injection.

BACKGROUND: There is a need to elucidate what affects the implantation and early pregnancy course in pregnancies conceived with assisted reproductive technology (ART) so that pregnancy rates and outcomes can be improved. Our aim was to determine the role of maternal Helicobacter pylori infection. MATERIAL AND METHODS: We did a prospective study of 187 infertile couples undergoing intracytoplasmic sperm injection (ICSI) and segregated those according to underlying infertility etiology. We assessed the status of H. pylori IgG antibodies and anti-CagA IgG antibodies by ELISA assay. All pregnancies were followed for early pregnancy loss (EPL, first 12 weeks). RESULTS: The likelihood of H. pylori infection increased with age (1.01, 95% confidence interval [CI]: 1.0-1.13; P = 0.040) but there was no association with EPL. Women infected with CagA-positive strains were more likely to have EPL (19.39, 95% CI: 1.8-208.4; P = 0.014). Women with tubal factor or ovulatory disorder infertility were more likely to abort early (12.95, 95% CI: 1.28-131.11; P = 0.030, 10.84, 95% CI: 1.47-80.03; P = 0.020, respectively). There was no association between EPL and age, number of embryos formed or transferred, or number of oocytes retrieved. CONCLUSION: Our findings suggest that infection with CagA-positive H. pylori strains is linked to an increase in women's potential to abort early (possibly through increased release of inflammatory cytokines). In addition, tubal factor and ovulatory disorder infertility are linked to EPL after ICSI due to unknown mechanisms. Proposals to eradicate H. pylori infection prior to ICSI could lead to a decrease in EPL after ART.

Transvaginal sonographic evaluation at different menstrual cycle phases in diagnosis of uterine lesions.

PURPOSE: Intrauterine lesions (IULs) are a common finding in women of reproductive age, particularly infertile women. Transvaginal sonography (TVS) is a popular tool for IUL detection, but there are conflicting data with respect to its accuracy. METHODS: Five hundred and six women were enrolled into the study. Of these, 496 underwent hysterosalpingography and subsequent TVS six different times during the course of their menstrual cycle. If a lesion was detected, it was further evaluated by sonohysterography (SHG) and hysteroscopy. RESULTS: Of 496 women, 41 were shown to have IULs by TVS and those lesions were confirmed in 39 by SHG and hysteroscopy. All 39 lesions were detectable during the ovulatory and early luteal phase (days 16-19) of the menstrual cycle. Accuracy of TVS during different phases was largely dependent on the size of the lesion. TVS falsely detected two lesions and missed fine adhesions in two patients. CONCLUSION: Accuracy of TVS in detection of IULs is highly dependent on the menstrual cycle phase, with the ovulatory and early luteal phase being the optimal time for this examination.

Spontaneous massive hemothorax secondary to chest wall chondrosarcoma: a case report.

We present the case of a 30-year-old man with no past history of disease or recent trauma, who was seen in the emergency room after developing sharp pain in the left hemithorax. Chest roentgenogram showed costopherenic angle blunting and an oval mass in the left mediastinum. A computed tomographic scan showed extrapleural mass with coarse calcifications and pleural effusion, confirmed by magnetic resonance imaging. The tumor was biopsied and removed during thoracotomy. The pathology reported revealed chondrosarcoma, which is a rare cause for a spontaneous massive hemothorax. Invasion of the intercostals vessels by the tumor was the probable cause of hemothorax in this patient.