Genomic alterations driving tumorigenesis result from the interaction of environmental exposures and endogenous cellular processes. With a diversity of risk factors, liver cancer is an ideal model to ...study these interactions. Here, we analyze the whole genomes of 44 new and 264 published liver cancers and we identify 10 mutational and 6 structural rearrangement signatures showing distinct relationships with environmental exposures, replication, transcription, and driver genes. The liver cancer-specific signature 16, associated with alcohol, displays a unique feature of transcription-coupled damage and is the main source of CTNNB1 mutations. Flood of insertions/deletions (indels) are identified in very highly expressed hepato-specific genes, likely resulting from replication-transcription collisions. Reconstruction of sub-clonal architecture reveals mutational signature evolution during tumor development exemplified by the vanishing of aflatoxin B1 signature in African migrants. Finally, chromosome duplications occur late and may represent rate-limiting events in tumorigenesis. These findings shed new light on the natural history of liver cancers.
Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main ...cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same individual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
Cyclins A2 and E1 regulate the cell cycle by promoting S phase entry and progression. Here, we identify a hepatocellular carcinoma (HCC) subgroup exhibiting cyclin activation through various ...mechanisms including hepatitis B virus (HBV) and adeno-associated virus type 2 (AAV2) insertions, enhancer hijacking and recurrent CCNA2 fusions. Cyclin A2 or E1 alterations define a homogenous entity of aggressive HCC, mostly developed in non-cirrhotic patients, characterized by a transcriptional activation of E2F and ATR pathways and a high frequency of RB1 and PTEN inactivation. Cyclin-driven HCC display a unique signature of structural rearrangements with hundreds of tandem duplications and templated insertions frequently activating TERT promoter. These rearrangements, strongly enriched in early-replicated active chromatin regions, are consistent with a break-induced replication mechanism. Pan-cancer analysis reveals a similar signature in BRCA1-mutated breast and ovarian cancers. Together, this analysis reveals a new poor prognosis HCC entity and a rearrangement signature related to replication stress.
Kallmann syndrome (KS) associates congenital hypogonadism due to gonadotropin-releasing hormone (GnRH) deficiency and anosmia. The genetics of KS involves various modes of transmission, including ...oligogenic inheritance. Here, we report that Nrp1(sema/sema) mutant mice that lack a functional semaphorin-binding domain in neuropilin-1, an obligatory coreceptor of semaphorin-3A, have a KS-like phenotype. Pathohistological analysis of these mice indeed showed abnormal development of the peripheral olfactory system and defective embryonic migration of the neuroendocrine GnRH cells to the basal forebrain, which results in increased mortality of newborn mice and reduced fertility in adults. We thus screened 386 KS patients for the presence of mutations in SEMA3A (by Sanger sequencing of all 17 coding exons and flanking splice sites) and identified nonsynonymous mutations in 24 patients, specifically, a frameshifting small deletion (D538fsX31) and seven different missense mutations (R66W, N153S, I400V, V435I, T688A, R730Q, R733H). All the mutations were found in heterozygous state. Seven mutations resulted in impaired secretion of semaphorin-3A by transfected COS-7 cells (D538fsX31, R66W, V435I) or reduced signaling activity of the secreted protein in the GN11 cell line derived from embryonic GnRH cells (N153S, I400V, T688A, R733H), which strongly suggests that these mutations have a pathogenic effect. Notably, mutations in other KS genes had already been identified, in heterozygous state, in five of these patients. Our findings indicate that semaphorin-3A signaling insufficiency contributes to the pathogenesis of KS and further substantiate the oligogenic pattern of inheritance in this developmental disorder.
A significant amount of wastewater is generated through the cleaning of equipment utilized within the ready mixed concrete production cycle. The reuse of concrete wash water as mix water is limited ...by the negative material performance impacts associated with the suspended solids; the effects are exacerbated with increasing solids contents and water aging. A novel carbon dioxide treatment to allow the use of high solids wash water (specific gravity 1.10) as mix water was examined. Seven batches of concrete were produced and compared: a reference mix, two batches with untreated wash water and four batches with CO2 treated wash water. The carbon dioxide treatment mineralized CO2 at 28% by mass of the treated solids. Acceptable concrete was produced through adjusting admixtures for workability. The compressive strength at 1, 7, 28 and 56 days was improved relative to both the reference and the concrete produced with untreated wash water. The suspended solids containing mineralized CO2 served as a viable cement replacement. The avoided cement and bound carbon dioxide served to lower the carbon impact of the concrete by about 14%. The approach allows three waste streams (CO2, wash water and wash water solids) to be reused to produce more sustainable concrete.
Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical ...variability is notable, for age of onset as well as severity and number of clinical manifestations. To identify genetic modifiers, we combined genome-wide approaches in 1070 clinically well-characterized FBN1 disease-causing variant carriers: (1) an FBN1 eQTL analysis in 80 fibroblasts of FBN1 stop variant carriers, (2) a linkage analysis, (3) a kinship matrix association study in 14 clinically concordant and discordant sib-pairs, (4) a genome-wide association study and (5) a whole exome sequencing in 98 extreme phenotype samples.Three genetic mechanisms of variability were found. A new genotype/phenotype correlation with an excess of loss-of-cysteine variants (P = 0.004) in severely affected subjects. A second pathogenic event in another thoracic aortic aneurysm gene or the COL4A1 gene (known to be involved in cerebral aneurysm) was found in nine individuals. A polygenic model involving at least nine modifier loci (named gMod-M1-9) was observed through cross-mapping of results. Notably, gMod-M2 which co-localizes with PRKG1, in which activating variants have already been described in thoracic aortic aneurysm, and gMod-M3 co-localized with a metalloprotease (proteins of extra-cellular matrix regulation) cluster. Our results represent a major advance in understanding the complex genetic architecture of MFS and provide the first steps toward prediction of clinical evolution.
Objectives: Survey studies are a commonly used method for data collection in surgical education research. Nevertheless, studies investigating survey design and response rates in surgical education ...research are lacking. The aim of this study was to gain an insight into survey response rates among surgical residents and medical students, and provide an initial reporting guideline for future survey studies in this field. Design: PubMed (MEDLINE) was systematically searched for survey studies in surgical education from January 2007 until February 2020, according to the PRISMA statements checklist. Study selection was conducted by 2 authors, independently. Surveys directed at surgical residents and/or medical students were included if data on response rates was available. Studies reporting solely from nonsurgical fields of medicine, paramedicine, or nursing were excluded. Subgroup analyses were performed, comparing response rates for varying modes of survey, per country, and for the 10 journals with the most identified surveys. Results: From the 5,693 records screened for a larger surgical survey database, a total of 312 surveys were included; 173 studies focused on surgical residents and 139 on medical students. The mean (SD) response rate was 55.7% (24.7%) for surgical residents and 69.0% (20.8%) for medical students. The number of published surveys increased yearly, mostly driven by an increase in surgical resident surveys. Although most surveys were Web-based (n = 166, 53.2%), this survey mode resulted in the lowest response rates (mean 52.6%). The highest response rates, with a mean of 79.8% (13.1%), were seen in in-person surveys (n = 89, 28.5%). Wide variations in response rates were seen between different countries and journals. Conclusions: Web-based surveys are gaining popularity for medical research in general and for surgical education specifically; however, this mode results in lower response rates than those of in-person surveys. The response rate of in-person surveys is especially high when focusing on medical students. To improve reporting of survey studies, we present the first step towards a reporting guideline.
A watch-and-wait strategy for patients with rectal cancer with a clinical complete response after neoadjuvant chemoradiotherapy is a valuable alternative for rectal resection. However, there are ...patients who will have residual tumor or regrowth during watch and wait.
The aim of this study was to investigate safety and costs for patients who underwent delayed surgery after neoadjuvant chemoradiotherapy.
This is a retrospective cohort study with prospectively collected data.
The study was conducted at a large teaching hospital.
Between January 2015 and May 2020, 622 new rectal cancer patients were seen, of whom 200 received neoadjuvant chemoradiotherapy. Ninety-four patients were included, 65 of whom underwent immediate surgery and 29 of whom required delayed surgery after an initial watch-and-wait approach.
Outcome measures included 30-day postoperative morbidity rate, hospital costs. 2-year overall and disease-free survival.
There was no difference in length of stay (9 vs 8; p = 0.83), readmissions (27.6% vs 10.0%; p = 0.10), surgical re-interventions (15.0% vs 3.4%; p = 0.16), or stoma-free rate (52.6% vs 31.0%; p = 0.09) between immediate and delayed surgery groups. Hospital costs were similar in the delayed group (€11,913 vs €13,769; p = 0.89). Two-year overall survival (93% vs 100%; p = 0.23) and disease-free survival (78% vs 81%; p = 0.47) rates were comparable.
Limitations included small sample size, follow-up time and retrospective design.
Delayed surgery for regrowth in a watch-and-wait program or for persistent residual disease after a repeated assessment is not associated with an increased risk of postoperative morbidity or a significant rise in costs compared to immediate total mesorectal excision. There also appears to be no evident compromise in oncological outcome. Repeated response assessment in patients with a near complete clinical response after neoadjuvant chemoradiotherapy is a useful approach to identify more patients who can benefit from a watch-and-wait strategy. See Video Abstract at http://links.lww.com/DCR/B836 .
ANTECEDENTES: Una estrategia de Watch and Wait para pacientes con cáncer de recto con una respuesta clínica completa después de quimiorradioterapia neoadyuvante es una alternativa valiosa en vez de resección rectal. Sin embargo, hay pacientes que tendrán tumor residual o un recrecimiento durante el Watch and Wait .OBJETIVO: El objetivo fue investigar la seguridad y los costos para los pacientes que se sometieron a una cirugía diferida después de la quimiorradioterapia neoadyuvante.DISEÑO: Este es un estudio de cohorte retrospectivo con datos recolectados prospectivamente.AJUSTE: El estudio se llevó a cabo en un gran hospital universitario.PACIENTES: Entre enero de 2015 y mayo de 2020, se atendieron 622 nuevos pacientes con cáncer de recto, de los cuales 200 recibieron quimiorradioterapia neoadyuvante. Se incluyeron 94 pacientes, de los cuales 65 se sometieron a cirugía inmediata y 29 pacientes requirieron cirugía diferida después de un enfoque inicial de observación y espera.PRINCIPALES MEDIDAS DE RESULTADO: se incluyeron la tasa de morbilidad posoperatoria a 30 días, los costos hospitalarios y las sobrevidas general y libre de enfermedad a dos años.RESULTADOS: No hubo diferencia en la duración de la estancia (9 vs 8, p = 0,83), reingresos (27,6% vs 10,0%, p = 0,10), reintervenciones quirúrgicas (15,0% vs 3,4%, p = 0,16) y tasa libre de estoma (52,6% vs 31,0%, p = 0,09) entre los grupos de cirugía inmediata y tardía. Los costos hospitalarios fueron similares en el grupo retrasado (11913 € frente a 13769 €, p = 0,89). Las tasas de sobrevida general a dos años (93% frente a 100%, p = 0,23) y sobrevida libre de enfermedad (78% frente a 81%, p = 0,47) fueron comparables.LIMITACIONES: Tamaño de muestra pequeño, tiempo de seguimiento y diseño retrospectivo.CONCLUSIÓN: La cirugía tardía para el recrecimiento en un programa de Watch and Wait o para la enfermedad residual persistente después de una evaluación repetida no se asocia con un riesgo mayor de morbilidad posoperatoria ni con un aumento significativo en los costos, en comparación con la escisión total de mesorrecto inmediata. Tampoco parece haber un compromiso evidente en el resultado oncológico. La evaluación repetida de la respuesta en pacientes con una respuesta clínica casi completa después de la quimiorradioterapia neoadyuvante es un enfoque útil para identificar más pacientes que pueden beneficiarse de una estrategia de Watch and Wait . Consulte Video Resumen en http://links.lww.com/DCR/B836 . (Traducción-Dr. Juan Carlos Reyes ).
Abstract
The COVID-19 pandemic caused by the new Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) continues to threaten public health and burden healthcare systems worldwide. Whole ...SARS-CoV-2 genome sequencing has become essential for epidemiological monitoring and identification of new variants, which could represent a risk of increased transmissibility, virulence, or resistance to vaccines or treatment. Different next-generation sequencing approaches are used in SARS-CoV-2 sequencing, although with different ability to provide whole genome coverage without gaps and to reliably detect new variants. In this study, we compared the performance of three target enrichment methods (two multiplex amplification methods and one hybridization capture) using nasopharyngeal swabs from infected individuals. We applied these target enrichment methods to the same set of nasopharyngeal samples (N = 93) in high-throughput mode. SARS-CoV-2 genome was obtained using short-read next-generation sequencing. We observed that each method has some advantages, such as high mapping rate (CleanPlex and COVIDSeq) or absence of systematic variant calling error (SureSelect) as well as their limitations such as suboptimal uniformity of coverage (CleanPlex), high cost (SureSelect) or supply shortages (COVIDSeq). Nevertheless, each of the three target enrichment kits tested in this study yielded acceptable results of whole SARS-CoV-2 genome sequencing and either of them can therefore be used in prospective programs of genomic surveillance of SARS-CoV-2. Genomic surveillance will be crucial to overcoming the ongoing pandemic of COVID-19, despite its successive waves and continually emerging variants.
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