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Internally located and oppositely oriented polymerase II promoters direct convergent transcription of a LINE-like retroelement, the Dictyostelium repetitive element, from Dictyostelium discoideum.

The Dictyostelium discoideum NC4 genome harbors approximately 150 individual copies of a retrotransposable element called the Dictyostelium repetitive element (DRE). This element contains nonidentical terminal repeats (TRs) consisting of conserved building blocks A and B in the left TR and B and C in the right TR. Seven different-sized classes of RNA transcripts from these elements were resolved by Northern (RNA) blot analysis, but their combined abundance was very low. When D. discoideum cells were grown in the presence of the respiratory chain blocker antimycin A, steady-state concentrations of these RNA species increased 10- to 20-fold. The D. discoideum genome contains two DRE subtypes, the full-length 5.7-kb DREa and the internally deleted 2.4-kb DREb. Both subtypes are transcribed, as confirmed by analysis of cloned cDNA. Primary transcripts from the sense strand originate at nucleotide +1 and terminate at two dominant sites, located 21 or 28 nucleotides upstream from the 3' end of the elements. The activity of a reasonably strong polymerase II promoter in the 5'-terminal A module is slightly upregulated by the tRNA gene located 50 +/- 4 nucleotides upstream and drastically reduced by the adjacent B module of the DRE. Transcripts from the opposite DNA strand (complementary-sense transcripts) were also detected, directed by an internally located polymerase II promoter residing within the C module. This latter transcription was initiated at multiple sites within the oligo(dA12) stretch which terminates DREs.

Animals↗

Complete Genome Sequencing of Occult Hepatitis B Virus in Hemodialysis Patients Reveals Subgenotype D2 and Immune Escape Mutations in Bangladesh.

Hepatitis B virus (HBV) remains a major global health concern, and occult HBV infection (OBI) presents significant diagnostic and clinical challenges, particularly among hemodialysis (HD) patients. This study is aimed at characterizing complete HBV genomes from maintenance HD patients with OBI in Bangladesh to elucidate genetic features, mutational patterns, and clinical implications. Serum samples from two HBsAg-negative HD patients were screened by ELISA and quantitative PCR. Viral DNA was amplified by PCR across four overlapping open reading frames (ORFs) and sequenced on the Illumina platform. Genome assembly, phylogenetic analysis, and mutational profiling were performed using reference datasets and bioinformatics tools. Antigenicity and hydrophilicity of HBsAg were predicted in silico. Both patients were anti-HBc and anti-HBs positive with high HBV DNA loads (2.29 × 1010 and 2.53 × 1010 copies/mL). Full-length genomes (3182 bp) were successfully sequenced and phylogenetic analysis showed both HBV genomes clustered within Genotype D, Subgenotype D2, and subtype ayw3, consistent with previously reported Bangladeshi HBV genomes. Comparative mutational analysis identified substitutions such as T1753C in the basal core promoter, C1845T in preC, and D144E within the "a" determinant of HBsAg, suggesting potential roles in vaccine escape, immune escape, and diagnostic failure. Several nonsynonymous mutations were also detected in polymerase, though none were potentially associated with antiviral resistance. Antigenicity and hydrophilicity profiles of HBsAg and its major hydrophilic region remained largely conserved. These findings demonstrate the persistence of OBI in HD patients and provide an initial indication of the need for genomic surveillance to monitor immune-escape mutations and improve HBV diagnostic strategies in endemic regions.

HBV genome sequencing↗

Impact of Tumor Genomic Profile on Adjuvant Chemotherapy Efficacy in Resected Pancreatic Adenocarcinoma: Results From the PRODIGE-24/CCTG PA6 Study.

PURPOSE: Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX/mFFX) is the standard adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC), offering survival benefits over gemcitabine (GEM). However, the contribution of molecular biomarkers to treatment selection remains unclear. Here, we characterize the molecular landscape of tumors from the PRODIGE-24/CCTG PA6 trial and assess the clinical impact of genomic alterations and molecular subtypes. PATIENTS AND METHODS: Tumor DNA sequencing was successfully performed in 317/350 tumors (168 mFFX; 149 GEM), complemented by transcriptomic subtyping using the PurIST classifier. Mutational status of four key PDAC driver genes and 24 homologous recombination repair (HRR)-associated genes was analyzed, alongside single-base substitution (SBS) mutational signatures. Primary and secondary end points were disease-free survival (DFS) and cancer-specific survival (CSS), respectively. RESULTS: In the mFFX group, the PurIST subtype was prognostic, with classical tumors showing superior DFS compared with basal-like tumors (stratified hazard ratio [sHR], 0.48 [95% CI, 0.31 to 0.77]). Among KRAS-mutated patients, mFFX significantly improved DFS compared with GEM (sHR, 0.60 [95% CI, 0.45 to 0.79]; P < .001), while no benefit was observed in KRAS wild-type tumors (interaction test, Pint. = 0.010). HRR and BRCA status were not predictive (Pint. = .568 and Pint. = .785, respectively). The benefit of mFFX was consistent across SBS-positive and SBS-negative subgroups. CONCLUSION: Overall, these results do not support a change in current adjuvant treatment strategies. mFFX remains the standard adjuvant regimen in PDAC, and the observed lack of benefit in KRAS wild-type tumors should be considered hypothesis-generating and warrants further investigation.

Humans↗

Epidemiological aspects of retrovirus (HTLV) infection among Indian populations in the Amazon Region of Brazil.

HTLV was initially described in association with a form of leukemia in Japan and a neurological disease in the Caribbean. It was soon shown that HTLV-II was endemic among Amerindians and particularly among Brazilian Indians. The Amazon Region of Brazil is presently the largest endemic area for this virus and has allowed several studies concerning virus biology, the search for overt disease, epidemiological data including detailed demographic data on infected individuals, clear-cut geographic distribution, definition of modes of transmission and maintenance within small, epidemiologically-closed groups, and advances in laboratory diagnosis of the infection. A new molecular subtype named HTLV-IIc was further described on the basis of genome sequencing and phylogenetic analysis. This subtype is present in other areas of Brazil, indicating that the virus is additionally both a valuable marker for tracing past human migration routes in the Americas and a probable marker for social habits of the present human population. HIV, the other human retrovirus, is still not prevalent among indigenous communities in the Brazilian Amazon, but these groups are also easy targets for the virus.

Adolescent↗

Personalized approach to infertility treatment in a patient with polyendocrine metabolic ovarian syndrome and chronic pancreatitis.

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in fertile women, with an estimated prevalence of 10-15%. It is a heterogeneous disease characterized by a complex pathogenesis. Genetic predisposition, neuroendocrine regulation disorders, and environmental influences play a key role. Dysregulation of the hypothalamic-pituitary-ovarian axis occurs with subsequent chronic anovulation, hyperandrogenemia, and metabolic abnormalities. Phenotypic variability reflects different pathophysiological mechanisms - based on genomic association studies, three subtypes of PCOS can be distinguished: reproductive, metabolic, and indeterminate. PCOS is one of the main causes of female infertility and a risk factor for the development of cardiometabolic diseases. Objective: The aim of the article is to summarize current recommendations of the European Society of Human Reproduction and Embryology (ESHRE 2023) regarding the diagnosis and treatment of polyendocrine metabolic ovarian syndrome (PMOS) in patients with fertility disorders and to demonstrate their practical application through a selected clinical case.

Humans↗

Expression of estrogen receptor (ER) subtypes and ERbeta isoforms in colon cancer.

Colon cancer incidence and mortality rates are lower in females compared with males, and numerous epidemiological studies suggest that estrogen replacement therapy (ERT) reduces cancer risk in postmenopausal women. Two estrogen receptor (ER) subtypes, ERalpha and ERbeta, mediate genomic effects in target cells. The aim of this study was to determine the relative mRNA expression levels for ER subtypes and ERbeta isoforms in colon tumors, normal colonic mucosa, and colon cancer cell lines. ERalpha and ERbeta isoform mRNA levels were investigated in paired samples of colon tumors and normal mucosa from 26 patients using comparative reverse transcription-PCR and then Southern analyses. Constitutive steroid hormone receptor mRNA levels were determined for five colon adenocarcinoma cell lines using reverse transcription-PCR, and ERbeta levels were further studied in Caco-2 cells using Northern and Western analyses. ERbeta mRNA steady-state levels (relative to glyceraldehyde-3-phosphate dehydrogenase mRNA) were significantly decreased in colon tumors compared with normal mucosa in female patients. ERbeta1 and ERbeta2 isoform mRNA levels were significantly decreased in tumors from female patients, and ERbeta1 mRNA levels were also significantly lower in tumors from female patients compared with tumors from males. ERalpha mRNA levels were much lower than ERbeta levels and were similar between normal mucosa and tumor samples in both genders. ERbeta mRNA was detected in Caco-2, T84, and SW1116 cell lines and all lines were essentially negative for ERalpha mRNA. Caco-2 cells coexpressed ERbeta1, ERbeta2, and ERbeta5 mRNA, though a single protein transcript was observed. ERbeta protein was detected in normal colonic superficial epithelium, vascular smooth muscle and endothelium, and enteric neurons by immunohistochemistry. These data show that ERbeta is the predominant ER subtype in the human colon and that decreased levels of ERbeta1 and ERbeta2 mRNA are associated with colonic tumorigenesis in females. This information suggests that activation of ERbeta-mediated processes in the superficial colonic epithelium may have a role in the preventive effects observed for female gender and ERT usage.

Adult↗

Seroincidence and phylogeny of human immunodeficiency virus infections in a cohort of commercial sex workers in Montevideo, Uruguay.

A cohort study involving 60 human immunodeficiency virus (HIV)-negative male transvestite commercial sex workers (CSWs) was conducted in Montevideo, Uruguay in 1999-2001. Serum samples were tested for HIV by an enzyme-linked immunosorbent assay screening with immunoblot confirmation. Six participants seroconverted for an incidence-density rate of 6.03 (95% confidence interval = 2.21-13.12) per 100 person-years. Inconsistent condom use during client sex (adjusted hazard ratio [AHR] = 6.7), during oral sex (AHR = 5.6), and at the last sexual encounter (AHR = 7.8), and use of marihuana (AHR = 5.4) were marginally associated with HIV seroconversion. Five samples were genotyped in the protease and reverse transcriptase regions; three were subtypes B and two were BF recombinants. Full genome analysis of four samples confirmed all three subtype B samples and one of the two BF recombinants. Male transvestite CSWs sustained a high rate of HIV infection. Larger prospective studies are required to better define subtypes and associated sexual and drug-related risk factors.

Adolescent↗

HIV-1 env sequence variation in brain tissue of patients with AIDS-related neurologic disease.

We investigated sequence variation in the human immunodeficiency virus type 1 (HIV-1) env gene region that encodes the fourth disulfide-bonded domain of the external membrane glycoprotein, gp120, among three HIV-1 isolates from patients with AIDS-related neurologic disease. The sequences of HIV-1 isolated directly from brain tissue, blood cells, and in vitro cell cultures were compared. The results suggest that there may be many closely related HIV-1 genomes of several distinct subtypes in an HIV-1-infected individual. Differences were observed in the frequency distribution of sequence variants obtained from brain versus blood of the same individuals. Overall, the proportion of silent mutations is much lower than expected by random occurrence. Taken together, these results favor the possibility that selective forces may play a role in the tissue distribution of certain HIV-1 strains.

AIDS Dementia Complex↗

[Methods of study of the hepatitis C virus genome. Diagnostic tools in human pathology].

The study of the molecular biology of infectious agents involves the examination of their genomes and the products of those genomes. Molecular biology methods may therefore allow us to study either DNAs or RNAs. The study of genomic RNAs (viruses) or messenger RNAs (all infectious agents) is used increasingly in infectious disease pathology. The hepatitis C virus was identified in 1989 and was shown to be responsible for a large number of chronic hepatitis cases in France and worldwide. This virus is a good model for the development of technologies to study RNAs, which will later be applied to the study of other viruses. The molecular biology methods used to study hepatitis C virus RNA may be classified into 3 categories. a) Detection methods evidence nucleic acids in fluid or tissue samples, mainly using the polymerase chain reaction (PCR), but also newly developed techniques, such as the NASBA (nucleic-acid-sequence-based amplification), the Q-beta reaction, and the LCR (ligase chain reaction), and techniques that localize viral RNAs in tissue (in situ hybridization, in situ PCR). b) Quantitative methods determine the amount of RNA present in a sample. These include quantitative PCR and new technologies based on signal amplification, such as the 'branched DNA' assays which have recently been developed. c) Qualitative analysis of the genome uses genotyping methods to classify viral strains into different genotypes and subtypes.

Genome, Viral↗

Genome characterisation of the newly discovered avian influenza A H5N7 virus subtype combination.

In Denmark, in 2003, a previously unknown subtype combination of avian influenza A virus, H5N7 (A/Mallard/Denmark/64650/03), was isolated from a flock of 12,000 mallards. The H5N7 subtype combination might be a reassortant between recent European avian influenza A H5, H7, and a third subtype, possibly an H6. The haemagglutinin and the acidic polymerase genes of the virus were closely related to a low-pathogenic Danish H5N2 virus A/Duck/Denmark/65041/04 (H5N2). The neuraminidase gene and the non-structural gene were most similar to the highly pathogenic A/Chicken/Netherlands/1/03 (H7N7) and the human-fatal A/Netherlands/219/03 (H7N7), respectively. The basic polymerase 1 and 2 genes were phylogenetically equidistant to both A/Duck/Denmark/65047/04 (H5N2) and A/Chicken/Netherlands/1/03 (H7N7). The nucleoprotein and matrix gene had highest nucleotide sequence similarity to the H6 subtypes A/Duck/Hong Kong/3096/99 (H6N2) and A/WDk/ST/1737/2000 (H6N8), respectively. All genes of the H5N7 strain were of avian origin, and no further evidence of pathogenicity to humans has been found.

Animals↗

Subtypes, genotypes and molecular epidemiology of the hepatitis B virus as reflected by sequence variability of the S-gene.

The serologic heterogeneity of the hepatitis B virus (HBV) has been established from immunodiffusion experiments for a long time. Four serotypes called subtypes of the hepatitis B surface antigen (HBsAg) have been defined by two mutually exclusive determinant pairs, d/y and w/r, and a common determinant a. These subtypes are adw, ayw, adr and ayr. By subdivision of the four major subtypes in the mid-70s, nine different subtypes were identified. Sequencing of viral genomes has now become a major goal of descriptive virology, and sequence data is now used to trace routes of infection, to reconstruct the phylogenetic history of viruses and two delimit genetic subtypes. A genetic classification based on the comparison of complete genomes has defined four genomic groups of HBV, later referred upon as genotypes, which were designated with A-D. However, the interrelation of the nine subtypes to the genotypes, the possible presence of more than four human HBV genotypes as well as their global geographical prevalence remained to be determined. By sequencing the S-gene of HBV the molecular basis was assessed for the serological variations of HBsAg within the major four subtypes. Thereby, also two new genotypes of HBV designated with E and F were identified. Complete genomic sequencing of E and F strains confirmed their status as new genotypes. The F genotype was found to diverge from other HBV genomes sequenced by 14%, thus being the most divergent HBV genome so far characterized. When the worldwide molecular epidemiology of HBV based on the variability of the S-gene was defined, the E and F strains seemed to originate in aboriginal populations of Africa and the New World, respectively. They shared a unique substitution at residue 140 in the second immunodominant loop of their encoded surface antigen when compared to the vaccine strain. Future research will establish whether this substitution may predispose to a vaccine escape mutant at residue 141, that now has been reported to occur in conjunction with the 140 substitution.

Demography↗

[Development of "Amplisens-HCV-genotype" reagent set for identification of hepatitis C virus genotypes 1a, 1b, 2a and 3a].

Multiple alignments of 119 nucleotide sequences of isolates of hepatitis C virus (HCV) were carried out to choose the type-specific primers for the 5'-ultra-core fragment of viral genome for the purpose of detecting the HCV 1a, 1b, 2a, and 3a subtypes. A PCR kit of reagents was designed for the amplification of cDNA HCV with selected type-specific primers and for making the electrophoresis in agarous gel. The kit comprises the positive control samples, i.e. HCV genome fragments, subtypes 1a, 1b, 2a and 3a, cloned in the plasmid vector. 440 cDNAHCV samples were simultaneously tested by using the worked out reagents' set and according to the method of Ohno et al. The results were found to be concordant in 336 cases, and were discordant in 4 samples. A sequencing of the PCR products and phylogenetic analysis showed that 1 sample belonged to subtype 4a, 2 samples belonged to subtypes 2k and 1 sample--to subtype 31.

DNA Primers↗

The genomic organization of the rat AT1 angiotensin receptor.

The AT1 receptor subtype modulates all of the hemodynamic effects of the vasoactive peptide, angiotensin II. In this report, we investigate the genomic organization of this important receptor. A rat genomic library was screened with fragments from the 5' region of a previously cloned cDNA, pCa18b, encoding the rat AT1 receptor. Two lambda clones were isolated and the hybridizing restriction fragments were sequenced. Comparison of the genomic and cDNA sequences reveals that the rat AT1 receptor has three exons. Two of the exons encode 5' untranslated sequence while the third exon encompasses the entire coding region, a small portion of the 5' untranslated region and the entire 3' untranslated sequence. Further analysis of the genomic sequence 5' to the start site of pCa18b demonstrates typical sequence motifs found in many eukaryotic promoters including a TATA box, a cap site and a potential Sp1 binding site. Southern analysis of genomic DNA indicates that the AT1 receptor subtype represented by pCa18b is encoded by one gene within the rat genome.

Amino Acid Sequence↗

Shared genetic architecture between ADHD and intelligence varies across ADHD subtypes.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental condition frequently accompanied by cognitive difficulties. Although previous genetic studies have demonstrated substantial overlap between ADHD and intelligence, most have treated ADHD as a single phenotype. However, whether this shared genetic architecture differs across ADHD subtypes remains unclear. METHODS: We conducted a genome-wide cross-trait analysis integrating large-scale genome-wide association study (GWAS) datasets of overall ADHD, its subtypes-childhood ADHD, persistent ADHD, and late-diagnosed ADHD-and intelligence (total N&#x2009;>&#x2009;300,000). Genome-wide genetic correlations, polygenic overlap, local genetic correlations, and variant-level associations between ADHD phenotypes and intelligence were evaluated to characterize their shared genetic architecture. Shared variants were identified through cross-trait enrichment analyses and subsequently mapped to genes for functional annotation and gene-set enrichment. Bidirectional associations were evaluated using two-sample Mendelian randomization with sensitivity analyses. Additional GWAS datasets were used to validate the robustness of shared loci by assessing the consistency of effect directions. RESULTS: All ADHD phenotypes showed significant negative genetic correlations with intelligence (rg ranging from -0.3442 to -0.4205). Despite these modest genome-wide correlations, cross-trait analyses revealed substantial genetic overlap, including polygenic overlap, local genetic correlations, and variant-level associations. We identified 184 loci jointly associated with ADHD traits and intelligence, including 64 novel loci, whereas no shared loci were detected for persistent ADHD under the current analysis. Functional annotation revealed biologically distinct enrichment patterns across subtypes: childhood ADHD loci were linked to early neurodevelopmental processes, while late-diagnosed ADHD loci were enriched in synapse-related and neuronal signaling pathways. Mendelian randomization analyses suggested bidirectional associations, with stronger evidence supporting a directional association from intelligence to ADHD risk. Furthermore, these shared loci showed largely consistent effect directions across additional GWAS datasets, providing support for the robustness of the findings. CONCLUSIONS: The shared genetic architecture between ADHD and intelligence varies across ADHD subtypes, highlighting distinct biological pathways underlying cognitive heterogeneity in ADHD. These findings suggest that the relationship between ADHD liability and general cognitive ability is not uniform across ADHD subtypes and may inform future research on risk stratification and early identification in child and adolescent psychiatry.

Humans↗

Virtually full-length subtype F and F/D recombinant HIV-1 from Africa and South America.

For reliable classification of HIV-1 strains appropriate reference sequences are needed. The HIV-1 genetic subtype F has a wide geographic spread, causing significant epidemics in South America, Africa, and some regions of Europe. Previously only two full-length sequences of each of the HIV-1 subtype F subclusters F1 and F2 have been described. To extend the knowledge of subtype F variation on a complete genome level, three new virtually full-length F1 sequences were cloned and sequenced, two from Africa and one from South America. Comparison of the new and previously described sequences showed that monophyletic clustering of the subcluster F1 of subtype F is consistent and highly supported in all genome regions. Two additional full-length strains were shown to be mosaics of subtypes F and D. These epidemiologically unrelated F/D sequences showed similar chimeric structure, suggesting that they may represent a previously undescribed circulating recombinant form (CRF). This was supported by partial sequences from three additional unlinked F/D recombinants. Genetic distances in the phylogenetic trees suggest that the recombination event leading to the putative CRF occurred relatively long ago, close to the divergence of the F1 and F2 subclusters. Furthermore, all five F/D recombinants are linked to the Democratic Republic of Congo, suggesting that the original recombination event took place in central Africa.

Africa↗

Characterization and physical mapping of Molluscum contagiosum virus DNA and location of a sequence capable of encoding a conserved domain of epidermal growth factor.

DNA from Molluscum contagiosum virus (MCV) isolates was analysed by restriction endonuclease cleavage, revealing two virus subtypes. Physical maps of cleavage sites for BamHI, ClaI and HindIII were constructed, and found to differ extensively between the two subtypes. MCV DNA was similar to Orthopoxvirus DNA with respect to size, terminal cross-linking and the presence of inverted terminal repetitions, but did not hybridize with vaccinia virus DNA. The genomes of the two MCV subtypes cross-hybridized and were colinear except for two small regions. There was sequence homology between DNA from corresponding map regions of the MCV subtypes but, in contrast to Orthopoxvirus DNA, no conservation of restriction sites. A synthetic oligonucleotide probe representing a conserved domain of epidermal growth factor, alpha-transforming growth factor and the vaccinia growth factor identified equivalent regions of both MCV genomes as having the potential to encode this domain. This locus is similar to the position of the vaccinia growth factor gene in vaccinia virus DNA. Thus MCV may induce epidermal cell proliferation and tumourigenesis by expression of an epidermal growth factor-like polypeptide.

Amino Acid Sequence↗

Characterization of intersubtype recombinant HIV type 1 genomes using a nonradioactive heteroduplex tracking assay.

The HIV-1 epidemic is characterized by the dominance of distinct viral subtypes in different regions of the world, and intersubtype recombinants are common. Traditional subtyping methods analyze only a small fragment of the HIV-1 genome, so the true extent of diversity and recombination has been difficult to examine. We developed a heteroduplex tracking assay (HTA) to identify viral subtypes and rapidly detect recombinant HIV-1 genomes. By using probes that target seven regions across the HIV-1 genome, HTAs can identify intersubtype recombinants on the basis of the heteroduplex mobility pattern. We used this method to analyze HIV-1 strains from 12 patients from the United States and Kenya, comparing the results with those obtained by sequencing. HTA analysis correctly identified the subtype of each region of the genome, revealing that several isolates were recombinants. This method is suitable for studies of HIV-1 diversity and recombination in areas of the world where multiple subtypes are found.

DNA Probes↗

Evolution and heterogeneity of lethal metastatic bladder cancer subtypes.

Histological variation is a prognostic feature of metastatic urothelial cancer1-3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes.

Journal Article↗