Neuroblastoma is a cancer of the developing sympathetic nervous system that most commonly presents in young children and accounts for approximately 12% of pediatric oncology deaths. Here, we report ...on a genome-wide association study (GWAS) in a discovery cohort or 2,101 cases and 4,202 controls of European ancestry. We identify two new association signals at 3q25 and 4p16 that replicated robustly in multiple independent cohorts comprising 1,163 cases and 4,396 controls (3q25: rs6441201 combined P = 1.2x10-11, Odds Ratio 1.23, 95% CI:1.16-1.31; 4p16: rs3796727 combined P = 1.26x10-12, Odds Ratio 1.30, 95% CI: 1.21-1.40). The 4p16 signal maps within the carboxypeptidase Z (CPZ) gene. The 3q25 signal resides within the arginine/serine-rich coiled-coil 1 (RSRC1) gene and upstream of the myeloid leukemia factor 1 (MLF1) gene. Increased expression of MLF1 was observed in neuroblastoma cells homozygous for the rs6441201 risk allele (P = 0.02), and significant growth inhibition was observed upon depletion of MLF1 (P < 0.0001) in neuroblastoma cells. Taken together, we show that common DNA variants within CPZ at 4p16 and upstream of MLF1 at 3q25 influence neuroblastoma susceptibility and MLF1 likely plays an important role in neuroblastoma tumorigenesis.
Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with ...excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells. Here we investigate the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation and transcription factor binding sites. We show that SNP rs2168101 G>T is the most highly associated variant (combined P = 7.47 × 10(-29), odds ratio 0.65, 95% confidence interval 0.60-0.70), and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumour formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P = 0.028) in neuroblastoma primary tumours, and ablates GATA3 binding (P < 0.0001). We demonstrate allelic imbalance favouring the G-containing strand in tumours heterozygous for this SNP, as demonstrated both by RNA sequencing (P < 0.0001) and reporter assays (P = 0.002). These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumour cells.
People living with HIV have a high likelihood of at-risk alcohol use and are at increased risk for neurocognitive decline. The underlying mechanisms involved in HIV-associated neurocognitive disorder ...(HAND) are not completely understood. Previously, we showed that chronic binge alcohol (CBA) administration produced behavioral deficits in non antiretroviral therapy (ART)-treated simian immunodeficiency virus (SIV)-infected macaques. Moreover, we observed that CBA/SIV enhanced neuroinflammatory gene expression and attenuated growth factor signaling in the frontal cortex (FC) and basal ganglia, effects that were partially ameliorated by ART. We hypothesized that the neuroinflammatory and growth factor changes observed could be associated with alterations in opioid, tachykinin, and endocannabinoid gene expression. Furthermore, we proposed that gene expression patterns in peripheral blood mononuclear cells (PBMCs) could serve as an indicator of expression changes in the brain (FC). We examined gene expression patterns of opioid, tachykinin, and endocannabinoid systems in FC and PBMCs isolated from CBA/SIV macaques. Expression of targeted genes as determined by reverse transcription-quantitative polymerase chain reaction was analyzed in relation to CBA, ART, plasma, and brain viral loads (PVL and BVL, respectively) and compared with baseline (PBMC) or FC from SIV- controls. FC expression of
,
, and
was negatively associated with PVL (
= .03, .002, .05 respectively). FC expression of
was positively associated with CBA exposure (
= .05). PBMC expression of
was positively associated with CBA exposure; but negatively associated with combined CBA/ART exposure (
= .03). Our findings reflect the complex interactions of SIV, CBA, and ART in modulating opioid and tachykinin system gene expression. Contrary to our prediction, results did not reveal parallel changes (in magnitude or direction) in PBMC and FC gene expression. Further studies are warranted to determine the relevance of these transcriptional changes in modulating HAND-related behaviors resulting from at-risk alcohol use and HIV/SIV exposure.
The genetic aetiology of sporadic neuroblastoma is still largely unknown. We have identified diverse neuroblastoma susceptibility loci by genomewide association studies (GWASs); however, additional ...SNPs that likely contribute to neuroblastoma susceptibility prompted this investigation for identification of additional variants that are likely hidden among signals discarded by the multiple testing corrections used in the analysis of genomewide data. There is evidence suggesting the CDKN1B, coding for the cycle inhibitor p27Kip1, is involved in neuroblastoma. We thus assess whether genetic variants of CDKN1B are associated with neuroblastoma. We imputed all possible genotypes across CDKN1B locus on a discovery case series of 2101 neuroblastoma patients and 4202 genetically matched controls of European ancestry. The most significantly associated rs34330 was analysed in an independent Italian cohort of 311 cases and 709 controls. In vitro functional analysis was carried out in HEK293T and in neuroblastoma cell line SHEP‐2, both transfected with pGL3‐CDKN1B‐CC or pGL3‐CDKN1B‐TT constructs. We identified an association of the rs34330 T allele (‐79C/T) with the neuroblastoma risk (Pcombined = 0.002; OR = 1.17). The risk allele (T) of this single nucleotide polymorphism led to a lower transcription rate in cells transfected with a luciferase reporter driven by the polymorphic p27Kip1 promoter (P < 0.05). Three independent sets of neuroblastoma tumours carrying ‐79TT genotype showed a tendency towards lower CDKN1B mRNA levels. Our study shows that a functional variant, associated with a reduced CDKN1B gene transcription, influences neuroblastoma susceptibility.
While immune checkpoint blockade (ICB) has become a pillar of cancer treatment, biomarkers that consistently predict patient response remain elusive due to the complex mechanisms driving immune ...response to tumors. We hypothesized that a multi-dimensional approach modeling both tumor and immune-related molecular mechanisms would better predict ICB response than simpler mutation-focused biomarkers, such as tumor mutational burden (TMB).
Tumors from a cohort of patients with late-stage melanoma (
= 51) were profiled using an immune-enhanced exome and transcriptome platform. We demonstrate increasing predictive power with deeper modeling of neoantigens and immune-related resistance mechanisms to ICB.
Our neoantigen burden score, which integrates both exome and transcriptome features, more significantly stratified responders and nonresponders (
= 0.016) than TMB alone (
= 0.049). Extension of this model to include immune-related resistance mechanisms affecting the antigen presentation machinery, such as HLA allele-specific LOH, resulted in a composite neoantigen presentation score (NEOPS) that demonstrated further increased association with therapy response (
= 0.002).
NEOPS proved the statistically strongest biomarker compared with all single-gene biomarkers, expression signatures, and TMB biomarkers evaluated in this cohort. Subsequent confirmation of these findings in an independent cohort of patients (
= 110) suggests that NEOPS is a robust, novel biomarker of ICB response in melanoma.
The techniques of facial reanimation are continually evolving in search of the ideal method for rehabilitating the paralyzed face. In the past, alternative cranial nerve motor nuclei have been used ...to power facial musculature. The trigeminal nerve is gaining popularity as a promising nerve to drive facial motion, particularly in the lower face.
This article describes a low-tension technique of using the transposed facial nerve to the trigeminal nerve (masseteric branch) for facial reanimation.
Six patients over 2.5 years were treated with facial nerve translocation with division at the geniculate and direct neurorrhaphy to the motor branch of the masseter. Patients were evaluated by physical examination, measurement of oral commissure excursion using MEEI FACE-gram software, video assessment, Sunnybrook Facial Grading System, Facial Disability Index, and Facial Clinimetric Evaluation Scale (FaCE).
Patients demonstrated early motion within 4 months postoperatively and were placed into facial physical therapy. All demonstrated improvements in oral competence, strong oral commissure excursion with good symmetry, speech improvements, and variable results in facial tone. Synkinesis to the smile antagonists in the lower face was noted and treated with chemodenervation in three of six. No upper division synkinesis was noted.
The motor branch of the trigeminal nerve is an effective option for facial reanimation via facial nerve translocation and end-to-end neurorrhaphy. Variable results in facial tone were noted with excellent oral commissure excursion. This procedure is safe in the reoperated mastoid.
The purpose of the study is to determine whether administering healing touch (HT) is more effective than deep breathing (DB) for reducing acute care nurses’ stress during a shift. A randomized ...cluster trial assessed 150 nurses’ vital signs and Visual Analog Scale for Stress (VASS) levels pre, post, and at follow-up to achieve a power of .7 and medium affect size. Open-ended questions following the intervention enriched quantitative findings describing the experience, facilitators, and barriers to potential use in nursing. The generalized estimating equation 1 (GEE1) comparisons of mean change over time, found that nurses in the HT intervention, had significantly lower VASS stress scores at posttreatment (−0.95, p = .0002) and at follow-up (−0.73, p = .0144) than the DB group, and the respiratory rate (RR) rate differences were nearly significant at post-intervention and significant at follow-up, respectively (1.36, p = .0568 and −2.28, p = .0011), indicating lower RR after HT. These findings support the use of HT as an effective stress reduction strategy as a relevant strategy to sustain a viable nurse work force post-COVID-19.
Background
Immunotherapy agents are used to treat advanced head and neck lesions. We aim to elucidate relationship between immunotherapy and surgical wound complications.
Methods
Retrospective ...multi‐institutional case series evaluating patients undergoing ablative and flap reconstructive surgery and immunotherapy treatment. Main outcome: wound complications.
Results
Eight‐two (62%) patients received preoperative therapy, 89 (67%) postoperative, and 33 (25%) in both settings. Forty‐one (31%) patients had recipient site complications, 12 (9%) had donor site. Nineteen (14%) had major recipient site complications, 22 (17%) had minor. There was no statistically significant difference in complications based on patient or tumor‐specific variables. Preoperative therapy alone demonstrated increased major complications (odds ratio OR 3.7, p = 0.04), and trend to more donor site complications (OR 7.4, p = 0.06), however treatment in both preoperative and postoperative therapy was not.
Conclusions
Preoperative immunotherapy may be associated with increased wound complications. Controlled studies are necessary to delineate this association and potential risks of therapy.
Papillary thyroid carcinoma (PTC) is an uncommon tumor in the pediatric population. A limited number of studies have examined genetic mutations affecting the mitogen-activated protein kinase (MAPK) ...pathway in the pediatric population.
To examine mutations affecting this pathway in PTC in our pediatric population and compare the BRAF V600E mutation rates in pediatric and adult tumors.
Eighty-four patients, including 14 pediatric and 70 adult, with PTC were tested for the BRAF V600E mutation by using real-time polymerase chain reaction and sequencing. Additionally, we examined the rate of RAS point mutations with real-time polymerase chain reaction and rearrangements of RET/PTC1 and RET/PTC3 in the pediatric group with fluorescence in situ hybridization. Clinical and histologic data were compared as well.
Of 77 tumors that had an interpretable result, the BRAF V600E mutant was identified in 4 of 13 pediatric patients (31%) and 43 of 64 adult patients (67%), which was a significant difference (using Fisher exact test, P = .03). One pediatric and 6 adult cases did not reveal an interpretable result with melting curve analysis. One of these cases harbored a rare 3-base pair deletion mutation (c.1799_1801delTGA). Mutations in RAS genes were not seen in any pediatric tumors. One tumor with a RET/PTC1 rearrangement and another with RET/PTC3 were identified in the pediatric population (15%).
The rate of the BRAF V600E mutation in the pediatric population is significantly lower than that seen in the adult population. Mutations in RAS do not contribute significantly to pediatric PTC. This experience from our institution adds to the growing body of knowledge regarding tumor genetics in pediatric PTC.
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