More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (∼30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC ...predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRC's proximal occurrence (70–80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age), colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40 and then annually thereafter. Should CRC occur, subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC. Because 40–60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir‐Torre variant). LS explains only 10–25% of familial CRC.
Due to continued miniaturization, semiconductor-based components used in high-performance digital microelectronics are becoming increasingly sensitive to cosmic rays and solar particle events. In the ...context of high-altitude flight control systems based on fly-by-wire techniques, this may produce sensor noise or affect actuator control signals. Although the consequences so far have been simply reductions in aircraft performance, catastrophic scenarios may be envisioned. In this article, we propose a novel architecture for a fault-tolerant flight control system able to detect and compensate for cosmic ray-induced multiple-bit upsets that affect actuator control signals in modern fly-by-wire avionics systems while assuming that the actuator itself remains healthy. A fault detection and diagnosis procedure was designed using a geometric approach combined with an extended multiple-model adaptive estimation technique. This procedure is able to process multiple faulty actuator-control signals and identify their parameters. The parameters thus obtained are then used with a reconfigurable sliding-mode control to compensate for such errors by mobilizing the remaining actuators' healthy control signals. Lyapunov stability theory is used to analyze the closed-loop system stability. Simulation results using Matlab /Simulink showed the effectiveness of the proposed approach in the case of a system challenged with double faults.
Neurofibromatosis type 1 (NF1) is a common tumor-predisposition disorder due to germline mutations in the tumor suppressor gene NF1. A virtually pathognomonic finding of NF1 is the plexiform ...neurofibroma (PN), a benign, likely congenital tumor that arises from bi-allelic inactivation of NF1. PN can undergo transformation to a malignant peripheral nerve sheath tumor, an aggressive soft-tissue sarcoma. To better understand the non-NF1 genetic contributions to PN pathogenesis, we performed whole-exome sequencing, RNASeq profiling and genome-wide copy-number determination for 23 low-passage Schwann cell cultures established from surgical PN material with matching germline DNA. All resected tumors were derived from routine debulking surgeries. None of the tumors were considered at risk for malignant transformation at the time; for example, there was no pain or rapid growth. Deep (~500X) NF1 exon sequencing was also conducted on tumor DNA. Non-NF1 somatic mutation verification was performed using the Ampliseq/IonTorrent platform. We identified 100% of the germline NF1 mutations and found somatic NF1 inactivation in 74% of the PN. One individual with three PNs had different NF1 somatic mutations in each tumor. The median number of somatic mutations per sample, including NF1, was one (range 0-8). NF1 was the only gene that was recurrently somatically inactivated in multiple tumors. Gene Set Enrichment Analysis of transcriptome-wide tumor RNA sequencing identified five significant (FDR<0.01) and seven trending (0.01⩽FDR<0.02) gene sets related to DNA replication, telomere maintenance and elongation, cell cycle progression, signal transduction and cell proliferation. We found no recurrent non-NF1 locus copy-number variation in PN. This is the first multi-sample whole-exome and whole-transcriptome sequencing study of NF1-associated PN. Taken together with concurrent copy-number data, our comprehensive genetic analysis reveals the primacy of NF1 loss as the driver of PN tumorigenesis.
To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The ...most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-β deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.
The objective of the present study was to compare the enteric methane (CH4) emissions and milk production of spring-calving Holstein-Friesian cows offered either a grazed perennial ryegrass diet or a ...total mixed ration (TMR) diet for 10 wk in early lactation. Forty-eight spring-calving Holstein-Friesian dairy cows were randomly assigned to 1 of 2 nutritional treatments for 10 wk: 1) grass or 2) TMR. The grass group received an allocation of 17kg of dry matter (DM) of grass per cow per day with a pre-grazing herbage mass of 1,492kg of DM/ha. The TMR offered per cow per day was composed of maize silage (7.5kg of DM), concentrate blend (8.6kg of DM), grass silage (3.5kg of DM), molasses (0.7kg of DM), and straw (0.5kg of DM). Daily CH4 emissions were determined via the emissions from ruminants using a calibrated tracer technique for 5 consecutive days during wk 4 and 10 of the study. Simultaneously, herbage dry matter intake (DMI) for the grass group was estimated using the n-alkane technique, whereas DMI for the TMR group was recorded using the Griffith Elder feeding system. Cows offered TMR had higher milk yield (29.5 vs. 21.1kg/d), solids-corrected milk yield (27.7 vs. 20.1kg/d), fat and protein (FP) yield (2.09 vs. 1.54kg/d), bodyweight change (0.54kg of gain/d vs. 0.37kg of loss/d), and body condition score change (0.36 unit gain vs. 0.33 unit loss) than did the grass group over the course of the 10-wk study. Methane emissions were higher for the TMR group than the grass group (397 vs. 251 g/cow per day). The TMR group also emitted more CH4 per kg of FP (200 vs. 174g/kg of FP) than did the grass group. They also emitted more CH4 per kg of DMI (20.28 vs. 18.06g/kg of DMI) than did the grass group. In this study, spring-calving cows, consuming a high quality perennial ryegrass diet in the spring, produced less enteric CH4 emissions per cow, per unit of intake, and per unit of FP than did cows offered a standard TMR diet.
We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD ...trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD.
Background and purpose
The aim was to determine the genetic background of unknown muscular dystrophy in five French families.
Methods
Twelve patients with limb girdle muscular dystrophy or distal ...myopathy were clinically evaluated. Gene mutations were identified using targeted exon sequencing and mutated DNAJB6 was tested in vitro.
Results
Five patients presented with distal lower limb weakness whilst others had proximal presentation with a variable rate of progression starting at the mean age of 38.5 years. Two novel mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) as well as the previously reported c.279C>G (p.Phe93Leu, two families) mutation in DNAJB6 were identified. All showed a reduced capacity to prevent protein aggregation.
Conclusions
The mutational and phenotypical spectrum of DNAJB6‐caused muscle disease is larger than previously reported, including also dysphagia. The originally reported c.279C>G (p.Phe93Leu) mutation is now identified in four different populations and appears to be a mutational hotspot. Our report confirms that some DNAJB6 mutations cause distal‐onset myopathy and hence DNAJB6 defects should be considered broadly in dominant muscular dystrophy families.
Guidelines on prudent antimicrobial use in veterinary medicine have been developed to reduce inappropriate prescribing of antimicrobials. Such guidelines focus mainly on the clinical and ...pharmacological indications for prescribing. A questionnaire study of veterinary surgeons engaged in cattle practice was completed to determine if non-clinical issues influence the decision to prescribe antimicrobials, and to assess if pharmacological and non-pharmacological issues influence the choice of antimicrobial prescribed. Non-clinical issues, including issues related to professional stress, influenced the prescribing decision of the majority of respondents. However, the nature of the veterinarian–client relationship did not influence the prescribing behaviour of the majority of respondents. Pharmacological and non-pharmacological issues influenced the choice of antimicrobial prescribed. The veterinary surgeon's prior experience of a drug was considered ‘often’ or ‘always’ by 95.7 per cent of respondents when making this decision. The findings of this study have implications for the recognition and management of stress within the profession, and for the development of intervention strategies to reduce inappropriate antimicrobial prescribing.
The postovulatory rise in circulating progesterone (P4) concentrations is associated with increased pregnancy success in beef
and dairy cattle. Our study objective was to determine how elevated P4 ...alters endometrial gene expression to advance conceptus
development. Synchronized heifers were inseminated (Day 0) and randomly assigned to pregnant high P4 or to pregnant normal
P4. All high P4 groups received a P4-release intravaginal device on Day 3 after insemination that increased P4 concentrations
up to Day 7 ( P < 0.05). Tissue was collected on Day 5, 7, 13, or 16 of pregnancy, and endometrial gene expression was analyzed using the
bovine Affymetrix (Santa Clara, CA) microarrays. Microarray analyses demonstrated that the largest number of P4-regulated
genes coincided with the day when the P4 profiles were different for the longest period. Genes with the largest fold change
increase (such as DGAT2 and MSTN also known as GDF8 ) were associated with triglyceride synthesis and glucose transport, which can be utilized as an energy source for the developing
embryo. Temporal changes occurred at different stages of early pregnancy, with the greatest difference occurring between well-separated
stages of conceptus development. Validation of a number of genes by quantitative real-time PCR indicated that P4 supplementation
advances endometrial gene expression by altering the time ( FABP , DGAT2 , and MSTN ) or duration ( CRYGS ) of expression pattern for genes that contribute to the composition of histotroph.
A significant barrier to adoption of de-escalated treatment protocols for human papillomavirus-driven oropharyngeal cancer (HPV-OPC) is that few predictors of poor prognosis exist. We conducted the ...first large whole-genome sequencing (WGS) study to characterize the genetic variation of the HPV type 16 (HPV16) genome and to evaluate its association with HPV-OPC patient survival.
A total of 460 OPC tumor specimens from two large United States medical centers (1980-2017) underwent HPV16 whole-genome sequencing. Site-specific variable positions single nucleotide polymorphisms (SNPs) across the HPV16 genome were identified. Cox proportional hazards model estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival by HPV16 SNPs. Harrell C-index and time-dependent positive predictive value (PPV) curves and areas under the PPV curves were used to evaluate the predictive accuracy of HPV16 SNPs for overall survival.
A total of 384 OPC tumor specimens (83.48%) passed quality control filters with sufficient depth and coverage of HPV16 genome sequencing to be analyzed. Some 284 HPV16 SNPs with a minor allele frequency ≥1% were identified. Eight HPV16 SNPs were significantly associated with worse survival after false discovery rate correction (individual prevalence: 1.0%-5.5%; combined prevalence: 15.10%); E1 gene position 1053 HR for overall survival (HRos): 3.75, 95% CI 1.77-7.95; Pfdr = 0.0099; L2 gene positions 4410 (HRos: 5.32, 95% CI 1.91-14.81; Pfdr = 0.0120), 4539 (HRos: 6.54, 95% CI 2.03-21.08; Pfdr = 0.0117); 5050 (HRos: 6.53, 95% CI 2.34-18.24; Pfdr = 0.0030), and 5254 (HRos: 7.76, 95% CI 2.41–24.98; Pfdr = 0.0030); and L1 gene positions 5962 (HRos: 4.40, 95% CI 1.88-10.31; Pfdr = 0.0110) and 6025 (HRos: 5.71, 95% CI 2.43-13.41; Pfdr = 0.0008) and position 7173 within the upstream regulatory region (HRos: 9.90, 95% CI 3.05-32.12; Pfdr = 0.0007). Median survival time for patients with ≥1 high-risk HPV16 SNPs was 3.96 years compared with 18.67 years for patients without a high-risk SNP; log-rank test P < 0.001. HPV16 SNPs significantly improved the predictive accuracy for overall survival above traditional factors (age, smoking, stage, treatment); increase in C-index was 0.069 (95% CI 0.019-0.119, P < 0.001); increase in area under the PPV curve for predicting 5-year survival was 0.068 (95% CI 0.015-0.111, P = 0.008).
HPV16 genetic variation is associated with HPV-OPC prognosis and can improve prognostic accuracy.
•Few prognostic markers of human papillomavirus-driven oropharyngeal cancer (HPV-OPC) exist.•We conducted the first large HPV16 whole-genome sequencing study of 384 HPV16+OPCs•We found eight HPV16 SNPs to be strongly associated with HPV-OPC prognosis.•Median survival was 4 years for HPV-OPC patients with ≥1 high-risk HPV16 SNPs versus 19 years for patients without.•HPV16 SNPs improved predictive accuracy for HPV-OPC overall survival compared with age, stage, treatment and smoking alone.
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