Gene Rearrangement Research Articles

The complete mitochondrial genome of Dimorphopterus japonicus (Hidaka, 1959) (Hemiptera, Lygaeoidea) and phylogenetic relationships within the Lygaeoidea superfamily

Dimorphopterus japonicus is a kind of pest which seriously harms sorghum and millet. In this study, we sequenced the mitochondrial whole genome of D. japonicus (Hidaka, 1959), and characterized and analyzed the mitogenome. The D. japonicus genome length is 15,473 bp, and it exhibits a typical high A + T content (77.6%). The mitogenomic structure of D. japonicus is highly conservative and there are no gene rearrangements. The evolutionary rates of the PCGs are in the order of atp8 > nad3 > nad6 > nad2 > nad5 > atp6 > nad4 > nad4L > cox2 > nad1 > cytb > cox3 > cox1. By using the Bayesian inference and maximum likelihood methods, we inferred the phylogenetic relationships within Lygaeoidea and estimated their divergence times based on concatenated mitogenome genes. The stable clades of (Oxycarenidae + Piesmatidae), (Malcidae + Colobathristidae), (Meschiidae + Berytidae), and (Blissidae+(Cymidae + Ninidae)) were consistently recovered in all analyses. Estimated divergence times revealed that the divergence time of the Lygaeoidea was 99.4 Ma (95% HPD: 83.4-124.8 Ma), and most lygaeoid families diverged during the early Cretaceous to late Paleogene. Berytidae is the latest differentiation in the lygaeoid families, and the genus Dimorphopterus was differentiated in 45.9 Ma (95% HPD: 39.8–47.7 Ma). This study is of great significance for reconstructing the phylogeny of Lygaeoidea and providing insights into its evolutionary history.

Clinical and cytological characteristics of serous effusions in 69 cases of lymphoma patients.

To explore the value of cell morphology, immunophenotype, and gene alterations of serosal effusion in the diagnosis of lymphoma. Serosal effusion of 69 cases of lymphoma patients were collected, including 36 cases with malignant effusion and 33 cases with nonmalignant effusion. Ordinary cytology, liquid-based cytology, cellblock, and immunocytochemical staining were performed in each case, some cases were detected by fluorescence in situ hybridization for C-MYC, BCL2, and BCL6 gene translocations. T/B cell ratio in malignant and nonmalignant serosal effusions was analyzed and compared by flow cytometry (FCM)and immunohistochemical (IHC), respectively. The prognostic value of serous effusion in diffuse large B-cell lymphoma (DLBCL) was investigated and another 20 DLBCL cases without effusion were successively selected as control. The number of naive lymphocytes, apoptotic bodies, and mitotic figures were more common in malignant effusions compared with nonmalignant effusions (p < .01). The top three lymphomas in malignant effusion were DLBCL (19/36, 52.8%), mantle cell lymphoma (MCL) (4/36, 11.1%, 3 blastoid variant) and high-grade B-cell lymphoma (HGBL) (4/36, 11.1%). T/B cell ratio by FCM analysis ranged from 0.00 to 0.55 (mean 0.084) in malignant effusion, and 2.58 to 984.00 (mean 249.9) in nonmalignant effusion. The difference was significant (p = .017). The T/B cell ratio by IHC analysis ranged from 0.02 to 3.00 (mean 0.200) in malignant effusion, and 2.00-100.00 (mean 34.10) in nonmalignant effusion. The difference was significant (p = .017). In the effusions involving DLBCL, most effusions were present at the time of diagnosis (57.9%); single pleural effusions were more common (36.8%). The median overall survival times of patients with malignant effusion, nonmalignant effusion and DLBCL without serous effusion were 11, 17, and 23 months respectively (p = .04). Three patients of HGBL died, and the overall survival times were 5, 8, and 9 months, respectively. The cytomorphological characteristics combined with immunophenotype, FCM, gene rearrangement, and other tests can diagnose and classify patients with effusion as the first symptom. The T/B cell ratio is less than 1 by FCM or IHC suggesting a malignant serosal effusion. The presence of malignant effusion in DLBCL patients is an important clue for poor prognosis.

Ulcerative Jejunitis in Celiac Disease: A Thirty-Year U.S. Experience.

Ulcerative jejunitis (UJ) or ulcerative enteritis (UE) is a rare complication of celiac disease (CeD). Guidelines regarding diagnosis and management are missing and these cases have seldom been reported in the United States. Single center case-series of CeD in which UE developed at a large academic center in the USA. Clinical presentation, diagnosis, treatment, and evolution of disease were collected. Eight cases were identified (6M/2F, mean age 59.5 (38-77) years). Presentations included intestinal obstruction (n=3), GI hemorrhage (n=3), and malabsorption (n=2). Ulcers were present in the duodenum in 4 patients, and exclusively past the angle of Treitz in only 4 cases, which makes the term ulcerative enteritis (UE) more appropriate than UJ. Six out of eight had T-cell receptor (TCR) clonal gene rearrangements and two had definite aberrant T cells. Corticosteroids were tried in all patients without improvement and 5 underwent surgical resection. Three patients received cladribine. One patient received an autologous stem cell transplant, followed by ruxolitinib. Two were subsequently diagnosed with enteropathy-associated T-cell lymphoma (EATL), including one with cerebral EATL, and 1 died from hemophagocytic syndrome. Two are still alive, including one only on GFD and two were lost to follow-up after surviving at least 30 months post treatment. UE seems a more appropriate term to describe an ulcerative complication of CeD at high risk of obstruction or bleeding. Steroids were not effective. Treatment outcomes were variable, but with a 50% death rate.

MTOR inhibitor in the treatment of TFE-positive advanced maligmnant PEComa of the uterus: a case report and literature review.

The pre- and intra-operative diagnoses of malignant uterine vascular perivascular epithelioid cell tumors (PEComas) can be challenging, for which the literature is limited. Some cases have been shown to have TSC gene mutations or rearrangements of the MiT factor family, resulting in variable responses to mTOR inhibitors. We report a case of a TFE-positive malignant PEComa of the uterus with pulmonary metastases that responded favorably to the mTOR inhibitor, everolimus. A 52-year-old female underwent a total hysterectomy 5 years ago for suspected sub-serosal or broad ligament fibroids. The intraoperative pathologic diagnosis was leiomyosarcoma of the uterus and the postoperative diagnosis was malignant PEComa of the uterus. The patient declined genetic testing and further treatment. In December 2020 the patient presented with a pelvic mass and underwent open abdominal mass resection and pelvic adhesiolysis. The pathologic findings confirmed recurrent malignant PEComa of the uterus. The pulmonary lesions gradually progressed during the follow-up period, so treatment with everolimus was initiated. Close follow-up evaluation for nearly 3 years showed disease remission without recurrence or progression. The patient described herein had a TFE-positive uterine malignant PEComa with lung metastasis and responded well to the mTOR inhibitor, everolimus. Close follow-up in the last 3 years showed remission without recurrence or progression.

Myoid Hamartoma of the Breast With HMGA2 Rearrangement and Associated In-Situ and Invasive Carcinoma: Case Report and Review of Literature.

Myoid hamartoma of the breast is an uncommon benign breast neoplasm. We describe an unusual example of an in-situ and invasive carcinoma arising in a myoid hamartoma. We also describe the unique molecular findings in the myoid hamartoma and review the pertinent literature. In radiology studies, the mammogram showed increased density/attenuation, and the ultrasound revealed a change in the overall echogenicity with hyperechoic and anechoic areas. The stromal compartment contained smooth muscle bundles and adipose tissue on microscopic examination. The stromal cells showed HMGA2 gene rearrangement by fluorescence in-situ hybridization analysis and overexpression of HMGA2 by immunohistochemistry. The breast myoid hamartoma is likely underpinned by HMGA2 gene rearrangement and HMGA2 protein overexpression, which can be used as an ancillary test to diagnose this rare breast lesion. Although most myoid hamartomas have a benign clinical course, the likelihood of malignant transformation should always be considered.

The Type 1 Diabetes T Cell Receptor and B Cell Receptor Repository in the AIRR Data Commons: a practical guide for access, use and contributions through the Type 1 Diabetes AIRR Consortium.

Human molecular genetics has brought incredible insights into the variants that confer risk for the development of tissue-specific autoimmune diseases, including type 1 diabetes. The hallmark cell-mediated immune destruction that is characteristic of type 1 diabetes is closely linked with risk conferred by the HLA class II gene locus, in combination with a broad array of additional candidate genes influencing islet-resident beta cells within the pancreas, as well as function, phenotype and trafficking of immune cells to tissues. In addition to the well-studied germline SNP variants, there are critical contributions conferred by T cell receptor (TCR) and B cell receptor (BCR) genes that undergo somatic recombination to yield the Adaptive Immune Receptor Repertoire (AIRR) responsible for autoimmunity in type 1 diabetes. We therefore created the T1D TCR/BCR Repository (The Type 1 Diabetes T Cell Receptor and B Cell Receptor Repository) to study these highly variable and dynamic gene rearrangements. In addition to processed TCR and BCR sequences, the T1D TCR/BCR Repository includes detailed metadata (e.g. participant demographics, disease-associated parameters and tissue type). We introduce the Type 1 Diabetes AIRR Consortium goals and outline methods to use and deposit data to this comprehensive repository. Our ultimate goal is to facilitate research community access to rich, carefully annotated immune AIRR datasets to enable new scientific inquiry and insight into the natural history and pathogenesis of type 1 diabetes.

Tasurgratinib in patients with cholangiocarcinoma or gastric cancer: Expansion part of the first-in-human phase I study.

Fibroblast growth factor receptors (FGFRs) are a highly conserved family of transmembrane receptor tyrosine kinases with multiple roles in the regulation of key cellular processes. Specific FGFR mutations have been observed in several types of cancers, including gastric carcinoma and cholangiocarcinoma. Dose escalation data of 24 Japanese patients with solid tumors treated with Tasurgratinib (previously known as E7090), a potent, selective FGFR1-3 inhibitor, was reported in a phase I, first-in-human, single-center study. Based on the safety, pharmacokinetic, and pharmacodynamic profiles observed in this study, the recommended dose of 140 mg once daily was selected for the expansion part (Part 2), a multicenter expansion of the dose-finding study restricted to patients with tumors harboring FGFR gene alterations. Safety and preliminary efficacy were assessed in Part 2. Pharmacodynamic pharmacogenomic markers (serum phosphate, FGF23, and 1,25-(OH)2-vitamin D, circulating tumor DNA) and pharmacokinetic profiles were also evaluated. A total of 16 patients were enrolled in Part 2, six with cholangiocarcinoma and 10 with gastric cancer. The most common treatment-emergent adverse events were hyperphosphatemia, palmar-plantar erythrodysesthesia syndrome, and paronychia. Five partial responses (83.3%) in cholangiocarcinoma patients and one partial response (11.1%) in gastric cancer patients were observed; median progression-free survival was 8.26 months (95% confidence interval [CI] 3.84, not evaluable [NE]) and 3.25 months (95% CI 0.95, 4.86), and overall survival was 22.49 months (95% CI 6.37, NE) and 4.27 months (95% CI 2.23, 7.95), respectively, in the two groups. In conclusion, Tasurgratinib 140 mg has a tolerable safety profile with good clinical efficacy in patients with cholangiocarcinoma harboring FGFR2 gene rearrangements.

Epithelioid solitary fibrous tumors from CNS and soft tissues: an unusual morphologic variant

BackgroundSolitary fibroous tumors (SFTs) are distinctive soft tissue tumors characterized by rearrangements of NAB2-STAT6 gene, which are associated with thin-walled, branching, “staghorn”-shaped vessels. SFTs are originally classified as a type of hemangiopericytoma (HPC). Classical SFTs are composed of spindle to ovoid cells arranged haphazardly or in fascicles. Rarely, SFTs exhibit unusual morphological variants such as fat formation, giant cells, dedifferentiation, or epithelioid variant. The epithelioid cell variant, which is composed almost entirely of epithelioid cells and arranged in solid or nest patterns, is extremely rare and frequently malignant.Case presentationIn this study, we reported three cases of epithelioid SFTs (ESFTs) located in extrathoracic sites (right lateral ventricle, right lumbar, left pelvis). All the subjects in this study were elderly, with a predominance of female patients, accounting for two out of the three cases, and only one case involved a male patient. The tumor cells were entirely composed of epithelioid cells and exhibited positive for CD34 and STAT-6 markers. Ultimately, the majority of cases (two out of three) were diagnosed as malignant SFTs.ConclusionThis study aims to enhance the awareness of ESFTs. In these cases, irrespective of the onset location, the arrangement patterns of tumor cells, such as papillary structures and the morphology of epithelial-like cells, conspicuously lack the hallmark histological characteristics of Solitary Fibrous Tumors (SFTs). Consequently, it requires differential diagnosis from a plethora of malignant neoplasms. Moreover, the elevated malignancy level of this cohort of cases poses substantial diagnostic challenges to pathologists, compounding the complexity of accurate interpretation.

NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation.

Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1::MLF1 and NPM1::CCDC28A. NPM1::MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay. NPM1::CCDC28A is more localized to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. NPM1::CCDC28A cells were also sensitive to menin inhibition. Thus, our study provides experimental evidence that both NPM1::MLF1 and NPM1::CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 and menin may be a promising strategy for the NPM1-rearranged AML.

The mitochondrial genome sequences of eleven leafhopper species of Batracomorphus (Hemiptera: Cicadellidae: Iassinae) reveal new gene rearrangements and phylogenetic implications.

Batracomorphus is the most diverse and widely distributed genus of Iassinae. Nevertheless, there has been no systematic analysis of the genome structure and phylogenetic relationships of the genus. To determine the characteristics of the mitogenomes of Batracomorphus species as well as the phylogenetic relationships between them, we sequenced and compared the mitogenomes of 11 representative Batracomorphus species. The results revealed that the mitogenomes of the 11 Batracomorphus species exhibited highly similar gene and nucleotide composition, and codon usage compared with other reported mitogenomes of Iassinae. Of these 11 species, we found that the mitogenomes of four species were rearranged in the region from trnI-trnQ-trnM to trnQ-trnI-trnM, whereas the remaining species presented a typical gene order. The topologies of six phylogenetic trees were in agreement. Eurymelinae consistently formed paraphyletic groups. Ledrinae and Evacanthinae formed sister taxa within the same clade. Similarly, Typhlocybinae and Mileewinae consistently clustered together. All phylogenetic trees supported the monophyly of Iassinae, indicating its evolutionary distinctiveness while also revealing its sister relationship with Coelidiinae. Notably, the nodes for all species of the genus Batracomorphus were well supported and these taxa clustered into a large branch that indicated monophyly. Within this large branch, four Batracomorphus species with a gene rearrangement (trnQ-trnI-trnM) exhibited distinctive clustering, which divided the large branch into three minor branches. These findings expand our understanding of the taxonomy, evolution, genetics, and systematics of the genus Batracomorphus and broader Iassinae groups.

Haemoglobin Gene Repertoire in Teleost and Cichlid Fishes Shaped by Gene Duplications and Genome Rearrangements.

Haemoglobin is a key molecule for oxygen transport in vertebrates. It exhibits remarkable gene diversity in teleost fishes, reflecting adaptation to various aquatic environments. In this study, we present the dynamic evolution of haemoglobin subunit genes based on a comparison of high-quality genome assemblies of 24 vertebrate species, including 17 teleosts (of which six are cichlids). Our findings indicate that teleost genomes contain a range of haemoglobin genes, from as few as five in fugu to as many as 43 in salmon, with the latter being the largest repertoire found in vertebrates. We find evidence that the teleost ancestor had at least four Hbα and three or four Hbβ subunit genes, and that the current gene diversity emerged during teleost radiation, driven primarily by (tandem) gene duplications, genome compaction, and rearrangement dynamics. We provide insights into the genomic organisation of haemoglobin clusters in different teleost species. We further show that the evolution of paralogous rhbdf1 genes flanking both teleost clusters (LA and MN) supports the hypothesis for the origin of the LA cluster by rearrangement within teleosts, rather than by the teleost specific whole-genome duplication. We specifically focus on cichlid fishes, where adaptation to low oxygen environment plays role in species diversification. Our analysis of six cichlid genomes, including Pungu maclareni from the Barombi Mbo crater lake, for which we sequenced a representative genome, reveals 18-32 copies of the Hb genes, and elevated rates of non-synonymous substitutions compared to other teleosts. Overall, this work facilitates a deeper understanding of how haemoglobin genes contribute to the adaptive potential of teleosts.

Insights into phylogenetic relationships and gene rearrangements: complete mitogenomes of two sympatric species in the genus Rana (Anura, Ranidae).

Mitochondrial genomes (also known as mitogenomes) serve as valuable molecular markers and have found widespread applications in molecular biology and ecology. There is abundant sequence variation in vertebrate mitogenomes, and occasionally, they exhibit gene rearrangements. In this study, two Chinese endemic Rana species, Ranajiemuxiensis and Ranahanluica, were sequenced and analyzed to obtain their complete mitogenomes. The two species were sympatrically distributed in the Zhangjiajie National Forest Park, in Wulingyuan District, Zhangjiajie City, Hunan Province, China. The mitogenome of R.jiemuxiensis was 17,506 bp, while that of R.hanluica was 17,505 bp, each comprising 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), two ribosomal RNA genes (rRNAs), and a non-coding control region (D-loop). The gene content, nucleotide composition, and evolutionary rates of each mitogenome were analyzed and compared with those of congeners. A phylogenetic analysis based on 22 mitogenomes in Rana revealed that the two sympatric species were in two different lineages, indicating that they were genetically separated to a certain extent. Three types of gene rearrangement patterns were identified when examining the gene orders of the 22 Rana mitogenomes. Most of the species shared a second and dominant gene rearrangement pattern that originated from the first ancient pattern. A "tandem duplication - multiple deletion" hypothesis was proposed to explain the evolution of these different gene rearrangement patterns. This study provided valuable data references and enhanced our understanding of the phylogenetic implications and gene rearrangements of Rana species.

Cyclin-D1 rearrangement as a secondary event in the large cell transformation of splenic marginal zone lymphoma with a TP53 deletion.

IGH::CCND1 translocation has been implicated as a preliminary finding in mantle cell lymphoma (MCL) and plasma cell myeloma, with cyclin D1 over-expression by immunohistochemistry stain, without gene rearrangement, reported in other hematologic neoplasms. CCND1 rearrangement has been reported infrequently as a secondary event in high-grade B-cell lymphomas. We present the case of an elderly man who was found to have a splenic marginal zone lymphoma with a heterozygous TP53 deletion. Years later at the time of relapse, the patient acquired a CCND1 rearrangement, in addition to apersistent TP53 deletion. Sequencing of the two lymphomas demonstrated clonal relatedness of the two processes. To our knowledge, this is the first report of a splenic marginal zone lymphoma witha TP53 deletion at diagnosis, evolving into a large B-cell lymphoma with a CCND1 rearrangement.

PCR GeneScan Analysis of Rearranged Immunoglobulin or T-Cell Receptor Genes for Clonality Diagnostics in Suspect Lymphoproliferations.

Assessment of the presence of clonal lymphoproliferations via polymerase chain reaction (PCR)-based analysis of rearranged immunoglobulin (IG) or T-cell receptor (TR) genes is a valuable method in the diagnosis of suspect lymphoproliferative disorders. Additionally, this methodology can be used for evaluating dissemination of lymphoma cells and for studying the clonal relationship between multiple (different locations) and consecutive (over time) lymphomas. Here we describe an integrated approach to assess clonality via analysis of Ig heavy chain (IGH), Ig kappa (IGK), TCR beta (TRB), and TCR gamma (TRG) gene rearrangements, based on the standardized multiplex PCRs as originally developed by the European BIOMED-2 consortium (currently named EuroClonality). The described protocol covers the pre-analytical phase of DNA isolation (from formalin-fixed paraffin-embedded and fresh tissues, body fluids, peripheral blood, and bone marrow), the analytical phase of PCR GeneScan analysis, and the post-analytical interpretation of the obtained profiles, following established guidelines.

MRD Detection in B-Cell Non-Hodgkin Lymphomas Using Ig Gene Rearrangements and Chromosomal Translocations as Targets for Real-Time Quantitative PCR and ddPCR.

Minimal residual disease (MRD) diagnostics is of high clinical relevance in patients with indolent B-cell non-Hodgkin lymphomas (B-NHL), B-cell chronic lymphocytic leukemia (CLL), and multiple myeloma and serves as a surrogate parameter to evaluate treatment effectiveness and long-term prognosis. Real-time quantitative PCR (RQ-PCR) targeting circulating lymphoma cells is still the gold standard for MRD detection in indolent B-NHL and currently the most sensitive and the most broadly applied method in follicular lymphoma (FL) and mantle cell lymphoma (MCL). Alternatively, droplet digital PCR (ddPCR) can be used for MRD monitoring in multiple myeloma, mantle cell lymphoma, CLL, and FL with comparable sensitivity, accuracy, and reproducibility.The most broadly applicable MRD target in B-NHL is the junctional regions of the rearranged immunoglobulin heavy (IGH) and light chain genes. Complete and incomplete IGH and additionally IG kappa light chain rearrangements can be used as targets for MRD. Next-generation sequencing (NGS) of IG-rearrangements (IG-NGS) as new sequencing-based technology can overcome the limitation of PCR-based approaches and has a potential for higher sensitivity. Chromosomal translocations like the t(14;18)(q32;q21) translocation associated with IGH::BCL2 fusion in FL and t(11;14)(q13;q32) translocation in MCL leading to the IGH::CCND1 fusion can be used as MRD target in selected lymphoma subtypes. In patients with CLL, both flow-cytometry and RQ-PCR are equally suited for MRD assessment as long as a sensitivity of 10-4 is achieved.MRD diagnostics targeting the IG loci is complex and requires extensive knowledge and experience because the junctional regions of each clonal rearranged gene have to be identified before the patient-specific PCR assays can be designed for MRD monitoring. In addition, the presence and load of somatic hypermutation within the rearranged IGH gene occurring during B-cell development of germinal center and post-germinal center B-cell lymphomas may hamper appropriate primer binding leading to false-negative results. The translocations mentioned above have the advantage that consensus forward primers and probes, both placed in the breakpoint regions of chromosome 18 in FL and chromosome 11 in MCL, can be used in combination with a reverse primer placed in the IGH joining region of chromosome 14. PCR-based methods using allele-specific primers can reach a high sensitivity of up to 10-5. This chapter provides all relevant background information and technical aspects for the complete laboratory process from detection of the clonal IG gene rearrangements and the chromosomal translocations at diagnosis to the actual MRD measurements in clinical follow-up samples of B-NHL. However, it should be noted that MRD diagnostics for clinical treatment protocols has to be accompanied by regular international quality control rounds to ensure the reproducibility and reliability of the MRD results. This is available by the EuroMRD network ( https://euromrd.org ), a subgroup of ESHLO ( https://eslho.org ).

Human Anti-Glycan Reactivity is Driven by the Selection of B cells Utilizing Private Antibody Gene Rearrangements that are Affinity Maturated in Germinal Centers.

The human antibody repertoire is broadly reactive with carbohydrate antigens represented in the universe of all living things, including both the host/self-as well as the commensal microflora-derived glycomes. Here we have used BCR receptor cloning and expression together with single-cell transcriptomics to analyze the B cell repertoire to the ubiquitous N-acetyl-D-glucosamine (GlcNAc) epitope in human cohorts and dissect the immune phylogeny of this predominant class of antibodies. We find that circulating anti-GlcNAc B cells exhibiting canonical BMem phenotypes emerge rapidly after birth and couple this observation with evidence for germinal center-dependent affinity maturation of carbohydrate-specific B cell receptors in situ during early childhood. Direct analysis of individual B cell clonotypes reveals they exhibit strikingly distinct fine-specificity profiles for palettes of GlcNAc containing moieties. These results suggest that a generalized exposure to complex environmental glycans drives the steady state anti-glycan repertoire.

Sequence comparison of the mitochondrial genomes of five caridean shrimps of the infraorder Caridea: phylogenetic implications and divergence time estimation

BackgroundThe Caridea, affiliated with Malacostraca, Decapoda, and Pleocyemata, constitute one of the most significant shrimp groups. They are widely distributed across diverse aquatic habitats worldwide, enriching their evolutionary history. In recent years, considerable attention has been focused on the classification and systematic evolution of Caridea, yet controversies still exist regarding the phylogenetic relationships among families.MethodsHere, the complete mitochondrial genome (mitogenome) sequences of five caridean species, namely Heterocarpus sibogae, Procletes levicarina, Macrobrachium sp., Latreutes anoplonyx, and Atya gabonensis, were determined using second-generation high-throughput sequencing technology. The basic structural characteristics, nucleotide composition, amino acid content, and codon usage bias of their mitogenomes were analyzed. Selection pressure values of protein-coding genes (PCGs) in species within the families Pandalidae, Palaemonidae, and Atyidae were also computed. Phylogenetic trees based on the nucleotide and amino acid sequences of 13 PCGs from 103 caridean species were constructed, and divergence times for various families within Caridea were estimated.ResultsThe mitogenome of these five caridean species vary in length from 15,782 to 16,420 base pairs, encoding a total of 37 or 38 genes, including 13 PCGs, 2 rRNA genes, and 22 or 23 tRNA genes. Specifically, L. anoplonyx encodes an additional tRNA gene, bringing its total gene count to 38. The base composition of the mitogenomes of these five species exhibited a higher proportion of adenine-thymine (AT) bases. Six start codons and four stop codons were identified across the five species. Analysis of amino acid content and codon usage revealed variations among the five species. Analysis of selective pressure in Pandalidae, Palaemonidae, and Atyidae showed that the Ka/Ks values of PCGs in all three families were less than 1, indicating that purifying selection is influencing on their evolution. Phylogenetic analysis revealed that each family within Caridea is monophyletic. The results of gene rearrangement and phylogenetic analysis demonstrated correlations between these two aspects. Divergence time estimation, supported by fossil records, indicated that the divergence of Caridea species occurred in the Triassic period of the Mesozoic era, with subsequent differentiation into two major lineages during the Jurassic period.ConclusionsThis study explored the fundamental characteristics and phylogenetic relationships of mitogenomes within the infraorder Caridea, providing valuable insights into their classification, interspecific evolutionary patterns, and the evolutionary status of various Caridea families. The findings provide essential references for identifying shrimp species and detecting significant gene rearrangements within the Caridea infraorder.

The enigma of KMT2A gene in hematological disorders

Abstract Introduction/Objective Presence of distinct MLL rearrangements is an independent dismal prognostic factor. Rearrangements of the histone lysine [K]- MethylTransferase 2A gene (KMT2A) on chromosome 11q23, formerly known as the mixed-lineage leukemia (MLL) gene, are found in 10% and 5% of adult and children with acute leukemia respectively. Chromosome 11 breakpoints are typically localized to band 11q23.3, frequently altering the proto- oncogene KMT2A/MLL whereas partner chromosomes involved in translocation may vary. More than 80 different gene partners involved in this fusion have been described, although the majority of leukemias results from 6 common partner genes. KMT2A gene rearrangement are associated with poor prognosis in both Lymphoid and Myeloid leukemia. Methods/Case Report A retrospective study conducted in Cytogenetic laboratory of The Indus hospital, Karachi. All karyotype cases (age 1-60 year) with chromosome 11 aberrations were included from October 2020 to December 2022. Karyotype and FISH performed using G-banding and break a part probe for MLL respectively. Results (if a Case Study enter NA) Total of 923 cases received for karyotyping out of which 32(3.4%) cases were reported for 11q23 abnormalities. The median age was 5 (1.25-12.5) years, majority 15 (47%) were 1-10 years, 9(28%) were &amp;gt;10 years and 7(22%) were &amp;lt;1 years. M:F ratio was 1.9:1. B-ALL were 19(59.4%), AML 8(25%), and 5 (15.6%) were others. FISH performed in 23(72%) cases, 21 (91%) showed concordance with karyotype. The t(9;11) was the commonest 7(22%), followed by t(4;11) and (1;11). Chromosome 9 was the most common partner identified in B-ALL. Loss of 11q23 observed in 3 (13%) cases. Conclusion The findings underscore the heterogeneity of partner chromosomes involved in KMT2A gene rearrangements and emphasize the importance of employing both FISH and karyotyping for comprehensive detection. The high concordance rate between the two methods supports their complementary roles in clinical diagnostics. Understanding the specific translocations and partner chromosomes associated with MLL gene rearrangements contributes valuable insights for prognostication and targeted therapeutic strategies in acute leukemia. FISH and karyotype showed 91% concordance to detect this aberration.

Beamion LUNG-1, a Phase Ia/Ib trial of the HER2-specific tyrosine kinase inhibitor, zongertinib (BI 1810631), in patients with HER2-driven tumors: outcomes according to HER2 aberration type

Abstract Introduction/Objective Beamion LUNG-1 (NCT04886804) is an ongoing, Phase Ia/Ib trial evaluating the novel HER2- specific tyrosine kinase inhibitor, zongertinib, in patients with HER2 aberration-positive solid tumors (Phase Ia) and HER2 mutation-positive NSCLC (Phase Ib). Here, we report data from Phase Ia according to HER2 aberration type. Methods/Case Report Phase Ia enrolled patients with HER2 aberration-positive (by local assessment: gene mutations, rearrangements, amplification, or overexpression) advanced/metastatic solid tumors. Patients received escalating doses of zongertinib BID (≥15 mg) or QD (≥60 mg), guided by a Bayesian model with overdose control. The primary endpoint of Phase Ia was maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). Results (if a Case Study enter NA) At data cut-off (January 29, 2024), 83 patients received zongertinib (BID n=17; QD n=66). Three patients had DLTs during the MTD evaluation period (G3 decreased platelets, G3 diarrhea, G4 neutropenia); the MTD was not reached. Treatment-related adverse events (TRAEs; all/G3/G4/G5) were reported in 76%/8%/1%/0% of patients. Confirmed investigator-assessed ORR/DCR rates in evaluable patients/patients with NSCLC (n=74/n=41) were 35%/85% and 44%/93%; median duration of response was 12.7/15.8 months, respectively. Based on preliminary data, 43 patients were HER2 mutation-positive (TKD/non-TKD/unknown n=36/n=6/n=1; A775_G776insYVMA n=16; G778dupGSP insertions n=3; S310F n=2); 23 patients overexpressed HER2 (2+/3+); 17 had HER2 amplification; 3 patients had NRG1 fusions. ORR/DCR rates (regardless of confirmation) in patients with TKD mutation-positive, A775_G776insYVMA-positive, non-TKD mutation-positive, G778dupGSP-positive and S310F- positive tumors were 64%/97%, 69%/94%, 20%/100%, 33%/100% and 50%/100%, respectively. ORR/DCR rates (regardless of confirmation) in patients with HER2 overexpressing tumors (+/- amplification) were 39%/83%. Of the 3 patients with NRG1 fusions, one had a partial response and two had stable disease. Conclusion In this preliminary analysis, zongertinib showed promising activity across a broad range of tumor types with different HER2 aberrations, including aberrations that have historically been difficult to treat. Updated data will be presented.

Solid-basaloid Variant of Mammary Adenoid Cystic Carcinoma – Report of an Unusual Case with Literature Review

Abstract Introduction/Objective Adenoid cystic carcinoma (AdCC) of breast is a rare subtype of malignancy, constituting approximately 0.1% of all breast carcinomas. The solid-basaloid variant (SB-AdCC) is exceedingly uncommon. Here, we present such an unusual case of SB-AdCC. Methods/Case Report A 64-year-old woman who underwent screening mammography presented with abnormal findings, revealing a hypoechoic ovoid, lobulated nodule at 7:00 of the left breast, which prompted an ultrasound- guided biopsy. Histologically, the biopsy cores demonstrated a 9 mm infiltrative round, solid nests with focal “cribriforming” areas. It was composed of monomorphic basaloid epithelial cells with marked nuclear atypia and high mitotic count. High-grade ductal carcinoma in situ, solid papillary carcinoma, and nonspecific invasive carcinoma were in differentials. Immunohistochemical (IHC) staining expressed positivity for CD117 and CK 5/6, while p63, SMMHC, and synaptophysin were negative. MYB gene rearrangement confirmed by fluorescence in situ hybridization. As expected, the tumor lacked ER, PR, and HER2 expression by IHC. Left breast mastectomy and axillary lymph node dissection have been scheduled. Results (if a Case Study enter NA) NA Conclusion Per literature review, the mean age of SB-AdCC at diagnosis was 68 years (33-84 years) with an average tumor size of 25 mm (12-70 mm). It had more aggressive behavior, with a higher propensity for lymph node metastasis, locally recurrence, and distant metastasis. The median disease-free survival was 46.5 months versus 151.8 months in those with class AdCC. Notably, neovascularization has emerged as a strong independent predictor of outcome in SB-AdCC. Most patients were treated with surgical excision, axillary lymph node dissection, and/or adjuvant chemotherapy. Limited studies demonstrated that neoadjuvant chemotherapy may induce an excellent response. Furthermore, a distinct molecular mutation enriched in NOTCH and CREBBP genes has been identified, which could be novel potential therapeutic target. Thus, awareness of this extremely rare breast cancer subtype and accurate differentiation from other entities are paramount for appropriate management strategies.