Analyses of non-coding somatic drivers in 2,658 cancer whole genomes.

The discovery of drivers of cancer has traditionally focused on protein-coding genes1-4. Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers6,7, raise doubts about others and identify novel candidates, including point mutations in the 5' region of TP53, in the 3' untranslated regions of NFKBIZ and TOB1, focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

Immune phenotype-genotype associations in primary clear cell renal cell carcinoma and matched metastatic tissue.

Adjuvant immunotherapy has been recently recommended for patients with metastatic ccRCC, but there are no tissue biomarkers to predict treatment response in ccRCC. Potential predictive biomarkers are mainly assessed in primary tumor tissue, whereas metastases remain understudied. To explore potential differences between genomic alterations and immune phenotypes in primary tumors and their matched metastases, we analyzed primary tumors (PTs) of 47 ccRCC patients and their matched distant metastases (METs) by comprehensive targeted parallel sequencing, whole-genome copy number variation (CNV) analysis, determination of microsatellite instability (MSI) and tumor mutational burden (TMB). We quantified the spatial distribution of tumor-infiltrating CD8+ T cells, and co-expression of the T-cell-exhaustion marker TOX by digital immunoprofiling and quantified tertiary lymphoid structures (TLS). Most METs were pathologically "cold". Inflamed, pathologically "hot" PTs were associated with a decreased disease-free survival (DFS), worst for patients with high levels of CD8+TOX+ T cells. Interestingly, inflamed METs showed a relative increase of exhausted CD8+TOX+ T cells and increased accumulative size of TLS compared to PTs. Integrative analysis of molecular and immune phenotypes revealed BAP1 and CDKN2A/B deficiency to be associated with an inflamed immune phenotype. Our results highlight the distinct spatial distribution and differentiation of CD8+ T cells at metastatic sites, and the association of an inflamed microenvironment with specific genomic alterations.

First report of Ascochyta rabiei infections on endemic Turkish populations of Cicer bijugum and C. turcicum.

Ascochyta rabiei causes Ascochyta blight disease on C. arietinum as well as on annual C. reticulatum, C. pinnatifidum and C. judaicum and perennial C. montbretii, C. isauricum, C. ervoides species (Can et al. 2007; Frenkel et al. 2007; Ozkilinc et al. 2019; Peever et al. 2007; Tekin et al. 2018). During field survey studies carried out on annual Cicer spp. in June 2022, concentric ring-shaped lesions were observed on the stems and leaves of C. bijugum in Mardin province and C. turcicum in Elazig province. Cicer reticulatum and C. arietinum plants were also found in the location where C. bijugum was found. No disease symptoms were observed in other Cicer species, while C. bijugum had 32% disease incidence. The disease incidence among the C. turcicum population was 37.3 %, and no chickpea cultivation area was found near it. Diseased plant parts were surface sterilized, placed on ½ potato dextrose agar (PDA) and incubated at 24±2 oC in 12 hours light/dark photoperiod. Each symptomatic plant was considered as one isolate. Monosporic isolates were obtained and the same colony morphology developed from all plant parts of C. turcicum and C. bijugum. Spores were oblong and spore sizes were 10.73±0.62 µm (n=15) in length and 3.60±0.25 (n=15) µm in width, 10.64±0.98 (n=15) µm in length and 3.00±0.26 (n=15) µm in width for isolates obtained from C. turcicum and C. bijugum, respectively. Amplicons for all 40 isolates were generated with mating type (MAT) primers, and the ITS region was amplified and sequenced by using the ITS4 and ITS5 primers (Peever et al. 2007). For the MAT primers, a 700 bp amplicon was observed for all the 20 isolates obtained from C. bijugum conferring to MAT1.1 idiomorph. In contrast, for the isolates obtained from C. turcicum 14 isolates had a 700 bp amplicon for MAT1.1 and 6 isolates had a 500 bp amplicon for MAT1.2, thus representing both idiomorphs in a ~2:1 ratio. BLAST analysis of the ITS sequences showed 100% homology with the reference ITS sequences for A. rabiei except for 23 SVRC CT 09/22 and 23 SVRC CT 22/22 isolates showing 99.81 % similarity. All sequences were submitted to GenBank (OP967923, OP967924, OP967925, OP967926 and OP967927 for A. rabiei isolates from C. turcicum; OP981072, OP981073 and OP981074 for A. rabiei isolates from C. bijugum). A phylogenetic tree was constructed using MEGAX software and the Neighbor-Joining method, using the ITS sequences of A. rabiei, other Ascochyta spp. and Colletotrichum gloeosporioides. The A. rabiei isolates from C. turcicum and C. bijugum clustered together with A. rabiei sequences from the NCBI (Kumar et al. 2018). Twelve-day-old C. bijugum and C. turcicum seedlings were inoculated with 5 x 105 spore/mL concentration of spores from 5 C. turcicum and 3 C. bijugum isolates and put in plastic bags for 24 hours (Can et al. 2007). Pathogenicity tests were carried out in triplicate pots with four plants each for each isolate in a controlled climate chamber at 24±2 oC, 70% humidity under 12 hours light/dark conditions. The first symptoms were observed within 7 days after inoculation (dai) and severe Ascochyta blight symptoms developed on all plants by 21 dai. Cicer bijugum and C. turcicum are endemic Cicer species exhibiting narrow distribution in the Southeastern region of Republic of Türkiye. As a major biotic stress source, A. rabiei could be an important threat to Cicer spp (Abbo et al. 2003). To our knowledge, this is the first report of A. rabiei from C. bijugum and C. turcicum species.

ROS1 genomic rearrangements are rare actionable drivers in microsatellite stable colorectal cancer.

c-Ros oncogene 1, receptor tyrosine kinase (ROS1) genomic rearrangements have been reported previously in rare cases of colorectal cancer (CRC), yet little is known about the frequency, molecular characteristics, and therapeutic vulnerabilities of ROS1-driven CRC. We analyzed a clinical dataset of 40 589 patients with CRC for ROS1 genomic rearrangements and their associated genomic characteristics (Foundation Medicine, Inc [FMI]). We moreover report the disease course and treatment response of an index patient with ROS1-rearranged metastatic CRC. ROS1 genomic rearrangements were identified in 34 (0.08%) CRC samples. GOPC-ROS1 was the most common ROS1 fusion identified (11 samples), followed by TTC28-ROS1 (3 samples). Four novel 5' gene partners of ROS1 were identified (MCM9, SRPK1, EPHA6, P4HA1). Contrary to previous reports on fusion-positive CRC, ROS1-rearrangements were found exclusively in microsatellite stable (MSS) CRCs. KRAS mutations were significantly less abundant in ROS1-rearranged vs ROS1 wild type cases. The index patient presented with chemotherapy-refractory metastatic right-sided colon cancer harboring GOPC-ROS1. Molecularly targeted treatment with crizotinib induced a rapid and sustained partial response. After 15 months on crizotinib disseminated tumor progression occurred and KRAS Q61H emerged in tissue and liquid biopsies. ROS1 rearrangements define a small, yet therapeutically actionable molecular subgroup of MSS CRC. In summary, the high prevalence of GOPC-ROS1 and noncanonical ROS1 fusions pose diagnostic challenges. We advocate NGS-based comprehensive molecular profiling of MSS CRCs that are wild type for RAS and BRAF and patient enrollment in precision trials.

The Complete Chloroplast Genome Sequence of Cicer bijugum, Genome Organization, and Comparison with Related Species.

Background: Chickpea is one of Turkey's most significant legumes, and because of its high nutritional value, it is frequently preferred in human nourishment.Chloroplasts, which have their own genetic material, are organelles responsible for photosynthesis in plant cells and their genome contains non-trivial information about the molecular features and evolutionary process of plants. Objective: Current study aimed at revealing complete chloroplast genome sequence of one of the wild type Cicer species, Cicer bijugum, and comparing its genome with cultivated Cicer species, Cicer arietinum, by using bioinformatics analysis tools. Except for Cicer arietinum, there has been no study on the chloroplast genome sequence of Cicer species.Therefore, we targeted to reveal the complete chloroplast genome sequence of wild type Cicer species, Cicer bijugum, and compare the chloroplast genome of Cicer bijugum with the cultivated one Cicer arietinum. Methods: In this study, we sequenced the whole chloroplast genome of Cicer bijugum, one of the wild types of chickpea species, with the help Next Generation Sequencing platform and compared it with the chloroplast genome of the cultivated chickpea species, Cicer arietinum, by using online bioinformatics analysis tools. Results: We determined the size of the chloroplast genome of C. bijugum as 124,804 bp and found that C. bijugum did not contain an inverted repeat region in its chloroplast genome. Comparative analysis of the C. bijugum chloroplast genome uncovered thirteen hotspot regions (psbA, matK, rpoB, rpoC1, rpoC2, psbI, psbK, accD, rps19, ycf2, ycf1, rps15, and ndhF) and seven of them (matK, accD, rps19, ycf1, ycf2, rps15 and ndhF) could potentially be used as strong molecular markers for species identification. It has been determined that C. bijugum was phylogenetically closer to cultivated chickpea as compared to the other species. Conclusion: It is aimed that the data obtained from this study, which is the first study in which whole chloroplast genomes of wild chickpea species were sequenced, will guide researchers in future molecular, evolutionary, and genetic engineering studies with chickpea species.

Global-level population genomics reveals differential effects of geography and phylogeny on horizontal gene transfer in soil bacteria.

Although microorganisms are known to dominate Earth's biospheres and drive biogeochemical cycling, little is known about the geographic distributions of microbial populations or the environmental factors that pattern those distributions. We used a global-level hierarchical sampling scheme to comprehensively characterize the evolutionary relationships and distributional limitations of the nitrogen-fixing bacterial symbionts of the crop chickpea, generating 1,027 draft whole-genome sequences at the level of bacterial populations, including 14 high-quality PacBio genomes from a phylogenetically representative subset. We find that diverse Mesorhizobium taxa perform symbiosis with chickpea and have largely overlapping global distributions. However, sampled locations cluster based on the phylogenetic diversity of Mesorhizobium populations, and diversity clusters correspond to edaphic and environmental factors, primarily soil type and latitude. Despite long-standing evolutionary divergence and geographic isolation, the diverse taxa observed to nodulate chickpea share a set of integrative conjugative elements (ICEs) that encode the major functions of the symbiosis. This symbiosis ICE takes 2 forms in the bacterial chromosome-tripartite and monopartite-with tripartite ICEs confined to a broadly distributed superspecies clade. The pairwise evolutionary relatedness of these elements is controlled as much by geographic distance as by the evolutionary relatedness of the background genome. In contrast, diversity in the broader gene content of Mesorhizobium genomes follows a tight linear relationship with core genome phylogenetic distance, with little detectable effect of geography. These results illustrate how geography and demography can operate differentially on the evolution of bacterial genomes and offer useful insights for the development of improved technologies for sustainable agriculture.

Towards advancing scientific knowledge of climate change impacts on short-duration rainfall extremes.

A large number of recent studies have aimed at understanding short-duration rainfall extremes, due to their impacts on flash floods, landslides and debris flows and potential for these to worsen with global warming. This has been led in a concerted international effort by the INTENSE Crosscutting Project of the GEWEX (Global Energy and Water Exchanges) Hydroclimatology Panel. Here, we summarize the main findings so far and suggest future directions for research, including: the benefits of convection-permitting climate modelling; towards understanding mechanisms of change; the usefulness of temperature-scaling relations; towards detecting and attributing extreme rainfall change; and the need for international coordination and collaboration. Evidence suggests that the intensity of long-duration (1 day+) heavy precipitation increases with climate warming close to the Clausius-Clapeyron (CC) rate (6-7% K-1), although large-scale circulation changes affect this response regionally. However, rare events can scale at higher rates, and localized heavy short-duration (hourly and sub-hourly) intensities can respond more strongly (e.g. 2 × CC instead of CC). Day-to-day scaling of short-duration intensities supports a higher scaling, with mechanisms proposed for this related to local-scale dynamics of convective storms, but its relevance to climate change is not clear. Uncertainty in changes to precipitation extremes remains and is influenced by many factors, including large-scale circulation, convective storm dynamics andstratification. Despite this, recent research has increased confidence in both the detectability and understanding of changes in various aspects of intense short-duration rainfall. To make further progress, the international coordination of datasets, model experiments and evaluations will be required, with consistent and standardized comparison methods and metrics, and recommendations are made for these frameworks. This article is part of a discussion meeting issue 'Intensification of short-duration rainfall extremes and implications for flash flood risks'.

Non-linear regression models for time to flowering in wild chickpea combine genetic and climatic factors.

BACKGROUND: Accurate prediction of crop flowering time is required for reaching maximal farm efficiency. Several models developed to accomplish this goal are based on deep knowledge of plant phenology, requiring large investment for every individual crop or new variety. Mathematical modeling can be used to make better use of more shallow data and to extract information from it with higher efficiency. Cultivars of chickpea, Cicer arietanum, are currently being improved by introgressing wild C. reticulatum biodiversity with very different flowering time requirements. More understanding is required for how flowering time will depend on environmental conditions in these cultivars developed by introgression of wild alleles. RESULTS: We built a novel model for flowering time of wild chickpeas collected at 21 different sites in Turkey and grown in 4 distinct environmental conditions over several different years and seasons. We propose a general approach, in which the analytic forms of dependence of flowering time on climatic parameters, their regression coefficients, and a set of predictors are inferred automatically by stochastic minimization of the deviation of the model output from data. By using a combination of Grammatical Evolution and Differential Evolution Entirely Parallel method, we have identified a model that reflects the influence of effects of day length, temperature, humidity and precipitation and has a coefficient of determination of R2=0.97. CONCLUSIONS: We used our model to test two important hypotheses. We propose that chickpea phenology may be strongly predicted by accession geographic origin, as well as local environmental conditions at the site of growth. Indeed, the site of origin-by-growth environment interaction accounts for about 14.7% of variation in time period from sowing to flowering. Secondly, as the adaptation to specific environments is blueprinted in genomes, the effects of genes on flowering time may be conditioned on environmental factors. Genotype-by-environment interaction accounts for about 17.2% of overall variation in flowering time. We also identified several genomic markers associated with different reactions to climatic factor changes. Our methodology is general and can be further applied to extend existing crop models, especially when phenological information is limited.

Molecular Details Underlying Dynamic Structures and Regulation of the Human 26S Proteasome.

The 26S proteasome is the macromolecular machine responsible for ATP/ubiquitin dependent degradation. As aberration in proteasomal degradation has been implicated in many human diseases, structural analysis of the human 26S proteasome complex is essential to advance our understanding of its action and regulation mechanisms. In recent years, cross-linking mass spectrometry (XL-MS) has emerged as a powerful tool for elucidating structural topologies of large protein assemblies, with its unique capability of studying protein complexes in cells. To facilitate the identification of cross-linked peptides, we have previously developed a robust amine reactive sulfoxide-containing MS-cleavable cross-linker, disuccinimidyl sulfoxide (DSSO). To better understand the structure and regulation of the human 26S proteasome, we have established new DSSO-based in vivo and in vitro XL-MS workflows by coupling with HB-tag based affinity purification to comprehensively examine protein-protein interactions within the 26S proteasome. In total, we have identified 447 unique lysine-to-lysine linkages delineating 67 interprotein and 26 intraprotein interactions, representing the largest cross-link dataset for proteasome complexes. In combination with EM maps and computational modeling, the architecture of the 26S proteasome was determined to infer its structural dynamics. In particular, three proteasome subunits Rpn1, Rpn6, and Rpt6 displayed multiple conformations that have not been previously reported. Additionally, cross-links between proteasome subunits and 15 proteasome interacting proteins including 9 known and 6 novel ones have been determined to demonstrate their physical interactions at the amino acid level. Our results have provided new insights on the dynamics of the 26S human proteasome and the methodologies presented here can be applied to study other protein complexes.

Development of New SSR (Simple Sequence Repeat) Markers for Lentils (Lens culinaris Medik.) from Genomic Library Enriched with AG and AC Microsatellites.

Simple sequence repeat (SSR) markers are the major molecular tools for genetic and genomic researches that have been extensively developed and used in major crops. However, few are available for lentils (Lens culinaris M.), economically an important cool-season legume. The lack of informative simple sequence repeat (SSR) markers in lentil has been a major limitation for lentil molecular breeding studies. Therefore, in order to develop SSR markers for lentil, an enriched genomic libraries for AC and AG repeats were constructed from the Lens culinaris cv Kafkas. A total of 350 clones were inquired for the detection of SSRs. Of 350 clones, 68 had SSR motifs. In polymorphism analysis using 53 newly developed SSRs, a total of 144 alleles across 24 lentil cultivars were detected with an average of 4.64 per locus. The average heterozygosity was 0.588 and polymorphism information contents ranged from 0.194 to 0.895 with an average value of 0.520. These newly developed SSRs will constitute useful tools for molecular breeding, mapping, and assessments of genetic diversity and population structure of lentils.

xVis: a web server for the schematic visualization and interpretation of crosslink-derived spatial restraints.

The identification of crosslinks by mass spectrometry has recently been established as an integral part of the hybrid structural analysis of protein complexes and networks. The crosslinking analysis determines distance restraints between two covalently linked amino acids which are typically summarized in a table format that precludes the immediate and comprehensive interpretation of the topological data. xVis displays crosslinks in clear schematic representations in form of a circular, bar or network diagram. The interactive graphs indicate the linkage sites and identification scores, depict the spatial proximity of structurally and functionally annotated protein regions and the evolutionary conservation of amino acids and facilitate clustering of proteins into subcomplexes according to the crosslink density. Furthermore, xVis offers two options for the qualitative assessment of the crosslink identifications by filtering crosslinks according to identification scores or false discovery rates and by displaying the corresponding fragment ion spectrum of each crosslink for the manual validation of the mass spectrometric data. Our web server provides an easy-to-use tool for the fast topological and functional interpretation of distance information on protein complex architectures and for the evaluation of crosslink fragment ion spectra. xVis is available under a Creative Commons Attribution-ShareAlike 4.0 International license at http://xvis.genzentrum.lmu.de/.

Association mapping for five agronomic traits in the common bean (Phaseolus vulgaris L.).

BACKGROUND: The common bean is the most important grain legume and a major source of protein in many developing countries. We analysed the following traits: pod fibre (PF), seeds per pod (SPP), plant type (PT), growth habit (GH), and days to flowering (DF) for a set of diverse common bean accessions and determined whether such traits were associated with amplified fragment length polymorphism (AFLP), simple sequence repeat (SSR) and single nucleotide polymorphism (SNP) markers. RESULTS: In this study, 66 common bean genotypes were used and genotyped with 233 AFLP, 105 SNP and 80 SSR markers. The association analysis between markers and five traits was performed using a General Linear Model (GLM) in Trait Analysis by aSSociation, Evolution and Linkage (TASSEL). The population structure was determined using the STRUCTURE software, and seven groups (K = 7) were identified among genotypes. The associations for such traits were identified and quantified; 62 markers were associated with the five traits. CONCLUSION: This study demonstrated that association mapping using a reasonable number of markers, distributed across the genome and with the appropriate number of individuals harboured to detect DNA markers linked to the traits of PF, SPP, PT, GH and DF in common bean.

Editorial: The RNA revolution and cancer.

RNA biology has revolutionized cancer understanding and treatment, especially in endocrine-related malignancies. This editorial highlights RNA's crucial role in cancer progression, emphasizing its influence on tumor heterogeneity and behavior. Processes like alternative splicing and noncoding RNA regulation shape cancer biology, with microRNAs, long noncoding RNAs, and circular RNAs orchestrating gene expression dynamics. Aberrant RNA signatures hold promise as diagnostic and prognostic biomarkers in endocrine-related cancers. Recent findings, such as aberrant PI3Kδ splice isoforms and epithelial-mesenchymal transition-related lncRNA signatures, unveil potential therapeutic targets for personalized treatments. Insights into m6A-associated lncRNA prognostic models and the function of lncRNA LINC00659 in gastric cancer represents ongoing research in this field. As understanding of RNA's role in cancer expands, personalized therapies offer transformative potential in managing endocrine-related malignancies. This signifies a significant stride towards precision oncology, fostering innovation for more effective cancer care.

Tailoring p-Type Behavior in ZnO Quantum Dots through Enhanced Sol-Gel Synthesis: Mechanistic Insights into Zinc Vacancies.

The synthesis and control of properties of p-type ZnO is crucial for a variety of optoelectronic and spintronic applications; however, it remains challenging due to the control of intrinsic midgap (defect) states. In this study, we demonstrate a synthetic route to yield colloidal ZnO quantum dots (QD) via an enhanced sol-gel process that effectively eliminates the residual intermediate reaction molecules, which would otherwise weaken the excitonic emission. This process supports the creation of ZnO with p-type properties or compensation of inherited n-type defects, primarily due to zinc vacancies under oxygen-rich conditions. The in-depth analysis of carrier recombination in the midgap across several time scales reveals microsecond carrier lifetimes at room temperature which are expected to occur via zinc vacancy defects, supporting the promoted p-type character of the synthesized ZnO QDs.

Accessing metal-specific orbital interactions in C-H activation with resonant inelastic X-ray scattering.

Photochemically prepared transition-metal complexes are known to be effective at cleaving the strong C-H bonds of organic molecules in room temperature solutions. There is also ample theoretical evidence that the two-way, metal to ligand (MLCT) and ligand to metal (LMCT), charge-transfer between an incoming alkane C-H group and the transition metal is the decisive interaction in the C-H activation reaction. What is missing, however, are experimental methods to directly probe these interactions in order to reveal what determines reactivity of intermediates and the rate of the reaction. Here, using quantum chemical simulations we predict and propose future time-resolved valence-to-core resonant inelastic X-ray scattering (VtC-RIXS) experiments at the transition metal L-edge as a method to provide a full account of the evolution of metal-alkane interactions during transition-metal mediated C-H activation reactions. For the model system cyclopentadienyl rhodium dicarbonyl (CpRh(CO)2), we demonstrate, by simulating the VtC-RIXS signatures of key intermediates in the C-H activation pathway, how the Rh-centered valence-excited states accessible through VtC-RIXS directly reflect changes in donation and back-donation between the alkane C-H group and the transition metal as the reaction proceeds via those intermediates. We benchmark and validate our quantum chemical simulations against experimental steady-state measurements of CpRh(CO)2 and Rh(acac)(CO)2 (where acac is acetylacetonate). Our study constitutes the first step towards establishing VtC-RIXS as a new experimental observable for probing reactivity of C-H activation reactions. More generally, the study further motivates the use of time-resolved VtC-RIXS to follow the valence electronic structure evolution along photochemical, photoinitiated and photocatalytic reactions with transition metal complexes.

Orthopedic Management of Radial Tunnel Syndrome: A Diagnostic and Treatment Dilemma.

OBJECTIVE: The first-line treatment for radial tunnel syndrome is conservative despite limited evidence concerning its efficiency. Surgical release is indicated if nonsurgical measures fail. Radial tunnel syndrome cases may be misdiagnosed as the more common lateral epicondylitis, and misdiagnosing radial tunnel syndrome causes wrong treatment and, thus, the perpetuation or increase of the pain. Although radial tunnel syndrome is a rare disorder, such cases can be encountered in tertiary hand surgery centers. This study aimed to present our experience in diagnosing and managing patients with radial tunnel syndrome. MATERIAL AND METHODS: Eighteen patients (7 male, 11 female; mean age=41.5 years, age range=22-61) in whom radial tunnel syndrome was diagnosed and treated at a single tertiary care center were retrospectively reviewed and included. Previous diagnoses (wrong diagnosis, delayed diagnosis, missed diagnosis, and other), previous treatments for such diagnoses, and their results before presenting to our institution were recorded. The shortened disabilities of the arm, shoulder, and hand questionnaire score and visual analog scale score were recorded before the surgery and at the final follow-up appointment. RESULTS: All the patients included in the study underwent steroid injections. Eleven patients (11/18, 61%) benefited from steroid injection and conservative treatment. The remaining 7 patients refractory to conservative treatment were offered surgical treatment. Of these, 6 patients accepted surgery while 1 did not accept it. In all patients, the mean visual analog scale score significantly improved from 6.38 (range: 5-8) to 2.1 (range: 0-7) (P < .001). The mean quick-disabilities of the arm, shoulder, and hand questionnaire scores were significantly improved from 43.4 (range: 31.8-52.5) preoperatively to 8.7 (range: 0-45.5) at the final follow-up (P < .001). In the surgical treatment group, the mean visual analog scale score significantly improved from 6.1 (range: 5-7) to 1.2 (range: 0-4) (P < .001). The mean quick-disabilities of the arm, shoulder, and hand questionnaire scores were significantly improved from 37.4 (range: 31.2-45.5) preoperatively to 4.7 (range: 0-13.6) at the final follow-up (P < .001). CONCLUSION: Our experience has shown that satisfactory results can be obtained by surgical treatment for patients with radial tunnel syndrome refractory to nonsurgical treatment whose diagnosis is confirmed by a thorough physical examination.

The complete chloroplast genome of Cicer reticulatum and comparative analysis against relative Cicer species.

The chloroplast (cp) genome is an adequate genomic resource to investigate evolutionary relationships among plant species and it carries marker genes available for species identification. The Cicer reticulatum is one of perennial species as the progenitor of cultivated chickpeas. Although a large part of the land plants has a quadruple chloroplast genome organization, the cp genome of C. reticulatum consists of one LSC (Large Single Copy Region), one SSC (Small Single Copy Region), and one IR (Inverted Repeat) region, which indicates that it has an untypical and unique structure. This type of chloroplast genome belongs to the IR-lacking clade. Chloroplast DNA (cpDNA) was extracted from fresh leaves using a high salt-based protocol and sequencing was performed using DNA Nanoball Sequencing technology. The comparative analysis employed between the species to examine genomic differences and gene homology. The study also included codon usage frequency analysis, hotspot divergence analysis, and phylogenetic analysis using various bioinformatics tools. The cp genome of C. reticulatum was found 125,794 bp in length, with an overall GC content of 33.9%. With a total of 79 protein-coding genes, 34 tRNA genes, and 4 rRNA genes. Comparative genomic analysis revealed 99.93% similarity between C. reticulatum and C. arietinum. Phylogenetic analysis further indicated that the closest evolutionary relative to C. arietinum was C. reticulatum, whereas the previously sequenced wild Cicer species displayed slight distinctions across their entire coding regions. Several genomic regions, such as clpP and ycf1, were found to exhibit high nucleotide diversity, suggesting their potential utility as markers for investigating the evolutionary relationships within the Cicer genus. The first complete cp genome sequence of C. reticulatum will provide novel insights for future genetic research on Cicer crops.

CanIsoNet: a database to study the functional impact of isoform switching events in diseases.

Motivation: Alternative splicing, as an essential regulatory mechanism in normal mammalian cells, is frequently disturbed in cancer and other diseases. Switches in the expression of most dominant alternative isoforms can alter protein interaction networks of associated genes giving rise to disease and disease progression. Here, we present CanIsoNet, a database to view, browse and search isoform switching events in diseases. CanIsoNet is the first webserver that incorporates isoform expression data with STRING interaction networks and ClinVar annotations to predict the pathogenic impact of isoform switching events in various diseases. Results: Data in CanIsoNet can be browsed by disease or searched by genes or isoforms in annotation-rich data tables. Various annotations for 11 811 isoforms and 14 357 unique isoform switching events across 31 different disease types are available. The network density score for each disease-specific isoform, PFAM domain IDs of disrupted interactions, domain structure visualization of transcripts and expression data of switched isoforms for each sample is given. Additionally, the genes annotated in ClinVar are highlighted in interactive interaction networks. Availability and implementation: CanIsoNet is freely available at https://www.caniso.net. The source codes can be found under a Creative Common License at https://github.com/kahramanlab/CanIsoNet_Web. Supplementary information: Supplementary data are available at Bioinformatics Advances online.

Ex Vivo Drug Testing in Patient-derived Papillary Renal Cancer Cells Reveals EGFR and the BCL2 Family as Therapeutic Targets.

BACKGROUND: Immune checkpoint inhibitors and antiangiogenic agents are used for first-line treatment of advanced papillary renal cell carcinoma (pRCC) but pRCC response rates to these therapies are low. OBJECTIVE: To generate and characterise a functional ex vivo model to identify novel treatment options in advanced pRCC. DESIGN, SETTING, AND PARTICIPANTS: We established patient-derived cell cultures (PDCs) from seven pRCC samples from patients and characterised them via genomic analysis and drug profiling. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Comprehensive molecular characterisation in terms of copy number analysis and whole-exome sequencing confirmed the concordance of pRCC PDCs with the original tumours. We evaluated their sensitivity to novel drugs by generating drug scores for each PDC. RESULTS AND LIMITATIONS: PDCs confirmed pRCC-specific copy number variations such as gains in chromosomes 7, 16, and 17. Whole-exome sequencing revealed that PDCs retained mutations in pRCC-specific driver genes. We performed drug screening with 526 novel and oncological compounds. Whereas exposure to conventional drugs showed low efficacy, the results highlighted EGFR and BCL2 family inhibition as the most effective targets in our pRCC PDCs. CONCLUSIONS: High-throughput drug testing on newly established pRCC PDCs revealed that inhibition of EGFR and BCL2 family members could be a therapeutic strategy in pRCC. PATIENT SUMMARY: We used a new approach to generate patient-derived cells from a specific type of kidney cancer. We showed that these cells have the same genetic background as the original tumour and can be used as models to study novel treatment options for this type of kidney cancer.