Loss of SUV420H2-Dependent Chromatin Compaction Drives Right-Sided Colon Cancer Progression.

BACKGROUND & AIMS: Epigenetic processes regulating gene expression contribute markedly to epithelial cell plasticity in colorectal carcinogenesis. The lysine methyltransferase SUV420H2 comprises an important regulator of epithelial plasticity and is primarily responsible for trimethylation of H4K20 (H4K20me3). Loss of H4K20me3 has been suggested as a hallmark of human cancer due to its interaction with DNMT1. However, the role of Suv4-20h2 in colorectal cancer is unknown. METHODS: We examined the alterations in histone modifications in patient-derived colorectal cancer organoids. Patient-derived colorectal cancer organoids and mouse intestinal organoids were genetically manipulated for functional studies in patient-derived xenograft and orthotopic transplantation. Gene expression profiling, micrococcal nuclease assay, and chromatin immunoprecipitation were performed to understand epigenetic regulation of chromatin states and gene expression in patient-derived and mouse intestinal organoids. RESULTS: We found that reduced H4K20me3 levels occurred predominantly in right-sided patient-derived colorectal cancer organoids, which were associated with increased chromatin accessibility. Re-compaction of chromatin by methylstat, a histone demethylase inhibitor, resulted in reduced growth selectively in subcutaneously grown tumors derived from right-sided cancers. Using mouse intestinal organoids, we confirmed that Suv4-20h2-mediated H4K20me3 is required for maintaining heterochromatin compaction and to prevent R-loop formation. Cross-species comparison of Suv4-20h2-depleted murine organoids with right-sided colorectal cancer organoids revealed a large overlap of gene signatures involved in chromatin silencing, DNA methylation, and stemness/Wnt signaling. CONCLUSIONS: Loss of Suv4-20h2-mediated H4K20me3 drives right-sided colorectal tumorigenesis through an epigenetically controlled mechanism of chromatin compaction. Our findings unravel a conceptually novel approach for subtype-specific therapy of this aggressive form of colorectal cancer.

Reading Frame Retrieval of Genes: A New Parameter of Codon Usage Based on the Circular Code Theory.

Based on the circular code theory, we define a new function f that quantifies the property of reading frame retrieval (RFR) of genes from their codon usage. This RFR function f is computed on a massive scale in genes of genomes of bacteria, eukaryotes and archaea. By expressing f as a function of the mean number [Formula: see text] of codons per gene, a "universal" property is identified, whatever the kingdom: the reading frame retrieval is enhanced in large genes. By investigating this property according to the theory developed, a Spearman's rank correlation with a strong negative coefficient is observed between the codon usage dispersion d (from the uniform codon distribution [Formula: see text]) and the RFR function f, whatever the kingdom (p-values [Formula: see text] in bacteria, [Formula: see text] in eukaryotes and [Formula: see text] in archaea). Thus, the reading frame retrieval is enhanced with the codon usage dispersion. Furthermore, this approach identifies a "genome centre" from which emerge two distinct "genome arms": an upper arm and a lower arm, respectively, above and below the linear regression. The RFR function by itself or combined with classical methods (alignment, phylogeny) could also be a new approach to classify the genomes in the future.

Assessment of Early Therapy Response of Non-Hodgkin's and Hodgkin's Lymphoma Using B-Mode Ultrasound and Dynamic Contrast-Enhanced Ultrasound.

OBJECTIVES: Here we asked, whether contrast enhanced ultrasound (CEUS) enables to judge early treatment response in malignant lymphoma as a potential guidance for further treatment. METHODS: From May 2017 to May 2018, 21 patients with histologically confirmed diagnosis of lymphoma were examined by B-mode ultrasound (B-US) and CEUS at fixed early time points after commencing therapy (days [d] 0, 15 and 30 after therapy start) and contrast enhancement patterns in target lymphoma lesions were quantified using Bracco-VUE Box® (DCE-US). To estimate the potential value of CEUS-enhancement patterns for early response prediction, patients were grouped according to their best achieved actual response into complete remission (CR) patients, partial remission (PR) patients or progressive disease (PD) patients. RESULTS: Between d0, d15 and d30, CR-patients showed a median lymphoma shrinking by 34% in B-US. PD-patients experienced a median lymphoma size reduction by 44% on day 15, but lymphoma mass again increased by 20% between d15 and d30. In contrast, the median CEUS enhancement intensity, as assessed by the area under the curve (AUC) was increasing at d15 in CR and PD patients (CR to 152%, PD: to 126%), but decreased at d30 to 14% in CR patients and 22% in PD patients. CONCLUSIONS: While early response assessment using B-US might be useful to predict treatment response in lymphoma, CEUS and DCE-US-although often feasible-do not provide additional value in this regard.

Circular code motifs in the ribosome: a missing link in the evolution of translation?

The origin of the genetic code remains enigmatic five decades after it was elucidated, although there is growing evidence that the code coevolved progressively with the ribosome. A number of primordial codes were proposed as ancestors of the modern genetic code, including comma-free codes such as the RRY, RNY, or GNC codes (R = G or A, Y = C or T, N = any nucleotide), and the X circular code, an error-correcting code that also allows identification and maintenance of the reading frame. It was demonstrated previously that motifs of the X circular code are significantly enriched in the protein-coding genes of most organisms, from bacteria to eukaryotes. Here, we show that imprints of this code also exist in the ribosomal RNA (rRNA). In a large-scale study involving 133 organisms representative of the three domains of life, we identified 32 universal X motifs that are conserved in the rRNA of >90% of the organisms. Intriguingly, most of the universal X motifs are located in rRNA regions involved in important ribosome functions, notably in the peptidyl transferase center and the decoding center that form the original "proto-ribosome." Building on the existing accretion models for ribosome evolution, we propose that error-correcting circular codes represented an important step in the emergence of the modern genetic code. Thus, circular codes would have allowed the simultaneous coding of amino acids and synchronization of the reading frame in primitive translation systems, prior to the emergence of more sophisticated start codon recognition and translation initiation mechanisms.

Mediastinal Masses in Contrast-Enhanced Ultrasound - Retrospective Analysis of 58 Cases.

OBJECTIVES: To determine contrast enhancing features of mediastinal masses (ML) using transcutaneous contrast-enhanced ultrasound (CEUS). METHODS: Retrospective analysis of n = 58 patients with histologically confirmed ML, which were examined in the period from October 2005 to February 2018 using transcutaneous B-mode ultrasound and CEUS. In n = 29 (50%) histological confirmation was performed by ultrasound guided core-needle biopsy. The lesions were evaluated using CEUS in regard to the enhancement pattern (hyper-, iso-, hypoenhancement, non-enhancement, homogenous, inhomogenous) compared to enhancement of the spleen as an in vivo reference. RESULTS: N = 53 (91.4%) of ML were malignant (m) (lymphoma n = 36, metastasis n = 11, thymoma n = 2, teratoma n = 1, sarcoma n = 2, seminoma n = 1). In n = 5 (8.6%) cases there was a benign (b) histology (thyroid tissue n = 2, thymus residue n = 1, ganglioneurinoma n = 1, scar tissue: n = 1). In ultrasound, n = 53 (91.4%; (48 = m, 5 = b)) were hypoechoic, n = 5 (8.6%, (5 = m,0 = b)) hyperechoic. In CEUS, n = 35 lesions presented an arterial isoenhancement (60.3%; 33 = m, 2 = b). An arterial hypoenhancement had n = 21 (36.2%, (20 = m,1 = b)), and no enhancement showed n = 2 (3.5%, (0 = m, 2 = b) of the ML. A parenchymal isoenhancement was observed in n = 1 (1.7%, (1 = m, 0 = b)), a hypoenhancement in n = 54 (93.1%; 51 = m, 3 = b) of the patients and almost no enhancement in n = 3 ML (5.2%, (1 = m, 2 = b).) The enhancement was homogeneous in n = 26 (44.8%, (25 = m,1 = b)) cases, in n = 31 (53.5%, (28 = m,3 = b)) inhomogeneous and n = 1 (1.7%) benign lesion was exclusively cystic. CONCLUSION: In CEUS, mediastinal tumor formations showed variable arterial enhancement, followed by parenchymal hypoenhancement (wash-out).

Characterization of accessory genes in coronavirus genomes.

BACKGROUND: The Covid19 infection is caused by the SARS-CoV-2 virus, a novel member of the coronavirus (CoV) family. CoV genomes code for a ORF1a / ORF1ab polyprotein and four structural proteins widely studied as major drug targets. The genomes also contain a variable number of open reading frames (ORFs) coding for accessory proteins that are not essential for virus replication, but appear to have a role in pathogenesis. The accessory proteins have been less well characterized and are difficult to predict by classical bioinformatics methods. METHODS: We propose a computational tool GOFIX to characterize potential ORFs in virus genomes. In particular, ORF coding potential is estimated by searching for enrichment in motifs of the X circular code, that is known to be over-represented in the reading frames of viral genes. RESULTS: We applied GOFIX to study the SARS-CoV-2 and related genomes including SARS-CoV and SARS-like viruses from bat, civet and pangolin hosts, focusing on the accessory proteins. Our analysis provides evidence supporting the presence of overlapping ORFs 7b, 9b and 9c in all the genomes and thus helps to resolve some differences in current genome annotations. In contrast, we predict that ORF3b is not functional in all genomes. Novel putative ORFs were also predicted, including a truncated form of the ORF10 previously identified in SARS-CoV-2 and a little known ORF overlapping the Spike protein in Civet-CoV and SARS-CoV. CONCLUSIONS: Our findings contribute to characterizing sequence properties of accessory genes of SARS coronaviruses, and especially the newly acquired genes making use of overlapping reading frames.

Identification of a circular code periodicity in the bacterial ribosome: origin of codon periodicity in genes?

Three-base periodicity (TBP), where nucleotides and higher order n-tuples are preferentially spaced by 3, 6, 9, etc. bases, is a well-known intrinsic property of protein-coding DNA sequences. However, its origins are still not fully understood. One hypothesis is that the periodicity reflects a primordial coding system that was used before the emergence of the modern standard genetic code (SGC). Recent evidence suggests that the X circular code, a set of 20 trinucleotides allowing the reading frames in genes to be retrieved locally, represents a possible ancestor of the SGC. Motifs from the X circular code have been found in the reading frame of protein-coding regions in extant organisms from bacteria to eukaryotes, in many transfer RNA (tRNA) genes and in important functional regions of the ribosomal RNA (rRNA), notably in the peptidyl transferase centre and the decoding centre. Here, we have used a powerful correlation function to search for periodicity patterns involving the 20 trinucleotides of the X circular code in a large set of bacterial protein-coding genes, as well as in the translation machinery, including rRNA and tRNA sequences. As might be expected, we found a strong circular code periodicity 0 modulo 3 in the protein-coding genes. More surprisingly, we also identified a similar circular code periodicity in a large region of the 16S rRNA. This region includes the 3' major domain corresponding to the primordial proto-ribosome decoding centre and containing numerous sites that interact with the tRNA and messenger RNA (mRNA) during translation. Furthermore, 3D structural analysis shows that the periodicity region surrounds the mRNA channel that lies between the head and the body of the SSU. Our results support the hypothesis that the X circular code may constitute an ancestral translation code involved in reading frame retrieval and maintenance, traces of which persist in modern mRNA, tRNA and rRNA despite their long evolution and adaptation to the SGC.

The Relation Between k-Circularity and Circularity of Codes.

A code X is k-circular if any concatenation of at most k words from X, when read on a circle, admits exactly one partition into words from X. It is circular if it is k-circular for every integer k. While it is not a priori clear from the definition, there exists, for every pair [Formula: see text], an integer k such that every k-circular [Formula: see text]-letter code over an alphabet of cardinality n is circular, and we determine the least such integer k for all values of n and [Formula: see text]. The k-circular codes may represent an important evolutionary step between the circular codes, such as the comma-free codes, and the genetic code.

Imatinib dose reduction in major molecular response of chronic myeloid leukemia: results from the German Chronic Myeloid Leukemia-Study IV.

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.

Histological validation of pulmonary infarction detected with contrast-enhanced ultrasound in patients with negative computed tomography pulmonary angiogram: A case series.

OBJECTIVE: The purpose of this case series is to evaluate the diagnostic potential of contrast-enhanced ultrasound (CEUS) in patients with clinically suspected pulmonary embolism (PE), suspicious pleural lesions, and negative computed tomography pulmonary angiogram (CTPA). PATIENTS/METHODS: Between January 2017 and January 2018, we examined patients with an intermediate or a high-risk Wells score and a negative CTPA with lung B-mode ultrasound (LUS). In a total of six patients, pleural defects were identified and further examined by CEUS. Nonenhancing lesions or those with inhomogeneous enhancement were considered to be suspicious for an embolic event and biopsied for histological validation. The data analysis was retrospective. RESULTS: In LUS, the lesions had an average size of 2.4 cm (range 2-3 cm). Five were hypoechoic and one was complex. The shape was wedge shaped (n = 5) or round (n = 1), and the number was solitary (n = 4) or multiple (n = 2) with dorsobasal localization (n = 6). Three lesions were nonenhancing, and three had an inhomogeneous enhancement with areas with complete absence of enhancement. The histological examination showed pulmonary infarction in all six cases, and in one patient also cells of a lung carcinoma. CONCLUSION: Our case series demonstrates the diagnostic potential of CEUS for detecting peripheral pulmonary infarction in patients with clinically suspected PE and negative CTPA scan regarding PE. A histological validation or a narrow follow-up might be warranted in some cases.

Strong Comma-Free Codes in Genetic Information.

Comma-free codes constitute a class of circular codes, which has been widely studied, in particular by Golomb et al. (Biologiske Meddelelser, Kongelige Danske Videnskabernes Selskab 23:1-34, 1958a, Can J Math 10:202-209, 1958b), Michel et al. (Comput Math Appl 55:989-996, 2008a, Theor Comput Sci 401:17-26, 2008b, Inf Comput 212:55-63, 2012), Michel and Pirillo (Int J Comb 2011:659567, 2011), and Fimmel and Strüngmann (J Theor Biol 389:206-213, 2016). Based on a recent approach using graph theory to study circular codes Fimmel et al. (Philos Trans R Soc 374:20150058, 2016), a new class of circular codes, called strong comma-free codes, is identified. These codes detect a frameshift during the translation process immediately after a reading window of at most two nucleotides. We describe several combinatorial properties of strong comma-free codes: enumeration, maximality, self-complementarity and [Formula: see text]-property (comma-free property in all the three possible frames). These combinatorial results also highlight some new properties of the genetic code and its evolution. Each amino acid in the standard genetic code is coded by at least one strong comma-free code of size 1. There are 9 amino acids [Formula: see text] among 20 such that for each amino acid from S, its synonymous trinucleotide set (excluding the necessary periodic trinucleotides [Formula: see text]) is a strong comma-free code. The primeval comma-free RNY code of Eigen and Schuster (Naturwissenschaften 65:341-369, 1978) is a self-complementary [Formula: see text]-code of size 16. Furthermore, it is the union of two strong comma-free codes of size 8 which are complementary to each other.

Circular code motifs in genomes of eukaryotes.

A set X of 20 trinucleotides was identified in genes of bacteria, eukaryotes, plasmids and viruses, which has in average the highest occurrence in reading frame compared to its two shifted frames (Michel, 2015; Arquès and Michel, 1996). This set X has an interesting mathematical property as X is a circular code (Arquès and Michel, 1996). Thus, the motifs from this circular code X, called X motifs, have the property to always retrieve, synchronize and maintain the reading frame in genes. In this paper, we develop several statistical analyzes of X motifs in 138 available complete genomes of eukaryotes in which genes as well as non-gene regions are examined. Large X motifs (with lengths of at least 15 consecutive trinucleotides of X and compositions of at least 10 different trinucleotides of X among 20) have the highest occurrence in genomes of eukaryotes compared to its 23 large bijective motifs, its two large permuted motifs and large random motifs. The largest X motifs identified in eukaryotic genomes are presented, e.g. an X motif in a non-gene region of the genome Solanum pennellii with a length of 155 trinucleotides (465 nucleotides) and an expectation E=10(-71). In the human genome, the largest X motif occurs in a non-gene region of the chromosome 13 with a length of 36 trinucleotides and an expectation E=10(-11). X motifs in non-gene regions of genomes could be evolutionary relics of primitive genes using the circular code for translation. However, the proportion of X motifs (with lengths of at least 10 consecutive trinucleotides of X and compositions of at least 5 different trinucleotides of X among 20) in genes/non-genes of the 138 complete eukaryotic genomes is about 8. Thus, the X motifs occur preferentially in genes, as expected from the previous works of 20 years.

Maximal dinucleotide and trinucleotide circular codes.

We determine here the number and the list of maximal dinucleotide and trinucleotide circular codes. We prove that there is no maximal dinucleotide circular code having strictly less than 6 elements (maximum size of dinucleotide circular codes). On the other hand, a computer calculus shows that there are maximal trinucleotide circular codes with less than 20 elements (maximum size of trinucleotide circular codes). More precisely, there are maximal trinucleotide circular codes with 14, 15, 16, 17, 18 and 19 elements and no maximal trinucleotide circular code having less than 14 elements. We give the same information for the maximal self-complementary dinucleotide and trinucleotide circular codes. The amino acid distribution of maximal trinucleotide circular codes is also determined.

An extended genetic scale of reading frame coding.

The reading frame coding (RFC) of codes (sets) of trinucleotides is a genetic concept which has been largely ignored during the last 50 years. An extended definition of the statistical parameter PrRFC (Michel, 2014) is proposed here for analysing the probability (efficiency) of reading frame coding of usage of any trinucleotide code. It is applied to the analysis of the RFC efficiency of usage of the C(3) self-complementary trinucleotide circular code X identified in prokaryotic and eukaryotic genes (Arquès and Michel, 1996). The usage of X is called usage XU. The highest RFC probabilities of usage XU are identified in bacterial plasmids and bacteria (about 49.0%). Then, by decreasing values, the RFC probabilities of usage XU are observed in archaea (47.5%), viruses (45.4%) and nuclear eukaryotes (42.8%). The lowest RFC probabilities of usage XU are found in mitochondria and chloroplasts (about 36.5%). Thus, genes contain information for reading frame coding. Such a genetic property which to our knowledge has never been identified, may bring new insights in the origin and evolution of the genetic code.

The maximal C(3) self-complementary trinucleotide circular code X in genes of bacteria, eukaryotes, plasmids and viruses.

In 1996, a set X of 20 trinucleotides is identified in genes of both prokaryotes and eukaryotes which has in average the highest occurrence in reading frame compared to the two shifted frames (Arquès and Michel, 1996). Furthermore, this set X has an interesting mathematical property as X is a maximal C(3) self-complementary trinucleotide circular code (Arquès and Michel, 1996). In 2014, the number of trinucleotides in prokaryotic genes has been multiplied by a factor of 527. Furthermore, two new gene kingdoms of plasmids and viruses contain enough trinucleotide data to be analysed. The approach used in 1996 for identifying a preferential frame for a trinucleotide is quantified here with a new definition analysing the occurrence probability of a complementary/permutation (CP) trinucleotide set in a gene kingdom. Furthermore, in order to increase the statistical significance of results compared to those of 1996, the circular code X is studied on several gene taxonomic groups in a kingdom. Based on this new statistical approach, the circular code X is strengthened in genes of prokaryotes and eukaryotes, and now also identified in genes of plasmids. A subset of X with 18 or 16 trinucleotides is identified in genes of viruses. Furthermore, a simple probabilistic model based on the independent occurrence of trinucleotides in reading frame of genes explains the circular code frequencies and asymmetries observed in the shifted frames in all studied gene kingdoms. Finally, the developed approach allows to identify variant X codes in genes, i.e. trinucleotide codes which differ from X. In genes of bacteria, eukaryotes and plasmids, 14 among the 47 studied gene taxonomic groups (about 30%) have variant X codes. Seven variant X codes are identified with at least 16 trinucleotides of X. Two variant X codes XA in cyanobacteria and plasmids of cyanobacteria, and XD in birds are self-complementary, without permuted trinucleotides but non-circular. Five variant X codes XB in deinococcus, plasmids of chloroflexi and deinococcus, mammals and kinetoplasts, XC in elusimicrobia and apicomplexans, XE in fishes, XF in insects, and XG in basidiomycetes and plasmids of spirochaetes are C(3) self-complementary circular. In genes of viruses, no variant X code is found.

A genetic scale of reading frame coding.

The reading frame coding (RFC) of codes (sets) of trinucleotides is a genetic concept which has been largely ignored during the last 50 years. A first objective is the definition of a new and simple statistical parameter PrRFC for analysing the probability (efficiency) of reading frame coding (RFC) of any trinucleotide code. A second objective is to reveal different classes and subclasses of trinucleotide codes involved in reading frame coding: the circular codes of 20 trinucleotides and the bijective genetic codes of 20 trinucleotides coding the 20 amino acids. This approach allows us to propose a genetic scale of reading frame coding which ranges from 1/3 with the random codes (RFC probability identical in the three frames) to 1 with the comma-free circular codes (RFC probability maximal in the reading frame and null in the two shifted frames). This genetic scale shows, in particular, the reading frame coding probabilities of the 12,964,440 circular codes (PrRFC=83.2% in average), the 216 C(3) self-complementary circular codes (PrRFC=84.1% in average) including the code X identified in eukaryotic and prokaryotic genes (PrRFC=81.3%) and the 339,738,624 bijective genetic codes (PrRFC=61.5% in average) including the 52 codes without permuted trinucleotides (PrRFC=66.0% in average). Otherwise, the reading frame coding probabilities of each trinucleotide code coding an amino acid with the universal genetic code are also determined. The four amino acids Gly, Lys, Phe and Pro are coded by codes (not circular) with RFC probabilities equal to 2/3, 1/2, 1/2 and 2/3, respectively. The amino acid Leu is coded by a circular code (not comma-free) with a RFC probability equal to 18/19. The 15 other amino acids are coded by comma-free circular codes, i.e. with RFC probabilities equal to 1. The identification of coding properties in some classes of trinucleotide codes studied here may bring new insights in the origin and evolution of the genetic code.

Circular code in introns.

A massive statistical analysis based on the autocorrelation function of the circular code X observed in genes is performed on the (eukaryotic) introns. Surprisingly, a circular code periodicity 0 modulo 3 is identified in 5 groups of introns: birds, ascomycetes, basidiomycetes, green algae and land plants. This circular code periodicity, which is a property of retrieving the reading frame in (protein coding) genes, may suggest that these introns have a coding property. In a well-known way, a periodicity 1 modulo 2 is observed in 6 groups of introns: amphibians, fishes, mammals, other animals, reptiles and apicomplexans. A mixed periodicity modulo 2 and 3 is found in the introns of insects. Astonishing, a subperiodicity 3 modulo 6 is a common statistical property in these 3 classes of introns. When the particular trinucleotides N1N2N1 of the circular code X are not considered, the circular code periodicity 0 modulo 3, hidden by the periodicity 1 modulo 2, is now retrieved in 5 groups of introns: amphibians, fishes, other animals, reptiles and insects. Thus, 10 groups of introns, taxonomically different, out of 12 have a coding property related to the reading frame retrieval. The trinucleotides N1N2N1 are analysed in the 216 maximal C3 self-complementary trinucleotide circular codes. A hexanucleotide code (words of 6 letters) is proposed to explain the periodicity 3 modulo 6. It could be a trace of more general circular codes at the origin of the circular code X.

Circular cut codes in genetic information.

In this work we present an analysis of the dinucleotide occurrences in the three codon sites 1-2, 2-3 and 1-3, based on a computation of the codon usage of three large sets of bacterial, archaeal and eukaryotic genes using the same method that identified a maximal C3 self-complementary trinucleotide circular code X in genes of bacteria and eukaryotes in 1996 (Arquès and Michel, 1996). Surprisingly, two dinucleotide circular codes are identified in the codon sites 1-2 and 2-3. Furthermore, these two codes are shifted versions of each other. Moreover, the dinucleotide code in the codon site 1-3 is circular, self-complementary and contained in the projection of X onto the 1st and 3rd bases, i.e. by cutting the middle base in each codon of X. We prove several results showing that the circularity and the self-complementarity of trinucleotide codes is induced by the circularity and the self-complementarity of its dinucleotide cut codes. Finally, we present several evolutionary approaches for an emergence of trinucleotide codes from dinucleotide codes.

Prospective Assessment of Treatment-Induced Liver Injury as a Cause of Diffuse Pathologic Hepatic Enhancement in Contrast-Enhanced Ultrasound.

OBJECTIVE: A hypo-enhancement of the liver in contrast-enhanced ultrasound (CEUS), pathologic one-minute hepatic enhancement (pOMHE), was recently observed in 70% of allogeneic hematopoietic stem cell transplantation patients with a high-risk profile for veno-occlusive disease (VOD). Whether pOMHE was a pre-clinical sign of VOD or an unspecific feature of liver damage secondary to intensive chemotherapy is unclear. METHODS: To investigate this, we studied CEUS patterns in patients receiving high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (auto-HSCT) or intensive induction therapy (IT) for the treatment of acute leukemia. From April 2020 to May 2021, patients undergoing auto-HSCT (n = 20) or acute leukemia patients prior to IT (n = 20) were included. All patients underwent a B-mode ultrasound and CEUS of the liver and spleen before treatment (d0) and on day 10 (d10) after therapy start. The one-minute hepatic enhancement was quantified. An optical density of liver enhancement less than 90% compared with the spleen was considered pathologic (pOMHE). Clinical and laboratory parameters used to assess a drug-induced liver injury (DILI) were documented. RESULTS: The OMHE was normal (d0 and d10) in 36 (90%) patients. After IT, 2 of 20 patients had a pOMHE. A DILI grade IV was diagnosed in one case and hyperfibrinolysis in the second case. In 2 of 20 (5%) auto-HSCT patients a pOMHE was observed at d10 without clinical symptoms. CONCLUSION: Chemotherapy-induced effects are not the cause of a pathologic liver enhancement. In contrast, severe DILI or hyperfibrinolysis can be associated with pOMHE.