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.

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.

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.

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.

Tracking C-H activation with orbital resolution.

Transition metal reactivity toward carbon-hydrogen (C-H) bonds hinges on the interplay of electron donation and withdrawal at the metal center. Manipulating this reactivity in a controlled way is difficult because the hypothesized metal-alkane charge-transfer interactions are challenging to access experimentally. Using time-resolved x-ray spectroscopy, we track the charge-transfer interactions during C-H activation of octane by a cyclopentadienyl rhodium carbonyl complex. Changes in oxidation state as well as valence-orbital energies and character emerge in the data on a femtosecond to nanosecond timescale. The x-ray spectroscopic signatures reflect how alkane-to-metal donation determines metal-alkane complex stability and how metal-to-alkane back-donation facilitates C-H bond cleavage by oxidative addition. The ability to dissect charge-transfer interactions on an orbital level provides opportunities for manipulating C-H reactivity at transition metals.

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.

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.

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.

Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma.

Defects in homologous recombination repair (HRR) in tumors correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harboring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient-derived sarcoma cells. Concomitantly, HRDhigh sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.

The Effect of Bone Morphology on Fracture Type and Treatment Result in Patients with Intertrochanteric Femur Fracture Aged over 65 year.

BACKGROUND: We aimed to investigate the effect of bone morphology on fracture type and treatment result in patient with inter-trochanteric fracture (IFF) treated with intramedullary nailing (IMN) aged over 65 years. Primary outcome of study was to investigate the relationship between fracture type (stable or unstable) and bone density. METHODS: This was a retrospective cohort study conducted at single trauma center which included patients aged >65 years, minimum 3 months' control postoperatively, patients with simple fall by evaluating the patient data from 2010 to 2021. All fractures were classified based on the AO classification system. Proximal femoral nail anti-rotation was used between 2010 and 2016, while InterTAN was used after 2016 in our clinic practice. For the evaluation of the bone morphology, we measured the canal-to-calcar ratio (CCR) and cortical thickness index (CTI) and classified with Dorr morphology on anteroposterior (AP) hip radiograph of both the fracture side and contralateral sides. Complications were also evaluated on radiological view. Failures were defined as non-union or failure of fixation. Excessive collapse and screw/blade prominence also evaluated by hip radiograph on the 3rd month control visit. RESULTS: One hundred and fifty females and 59 males were included in this study. The average age was 81.6±8.8 years. One hundred and forty-four patients were treated with InterTAN and 65 patients with helical blade type IMN (PFN-A®). There were 78 patients with stable IFF type A1 fracture and 131 patients with unstable IFF (109 patients with A2 and 22 patients with A3 AO type fracture). The mean CTI was 0.469±0.09 and 0.510±0.09 in the fracture and unaffected side femurs, respectively (p<0.001), the CCR was 0.636±0.15 and 0.568±12 in the fracture and unaffected side femurs, respectively (p<0.001). There were 36 patients with Dorr type A, 115 patients with Dorr type B, and 48 patients with Dorr type C in fracture side and 65 patients with Dorr type A, 123 patients with Dorr type B, and 21 patients with Dorr type C in non-affected side (p<0.001). There were 29 (13.9%) patients with screw (n=14) and blade (n=15) prominence. Excessive collapse was seen 30 patients (14.4%) and 16 patients (7.7) evaluated as a failure. CONCLUSION: We found a significant difference in the failure rate between unstable group than stable group which higher in unstable group according to the AO classification. In addition, the mean CTI, CCR, and Dorr index were significant difference in fractured side than unaffected side which indicated lower bone quality at fracture side.

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.

MTPpilot: An Interactive Software for Visualization of Next-Generation Sequencing Results in Molecular Tumor Boards.

PURPOSE: Comprehensive targeted next-generation sequencing (NGS) panels are routinely used in modern molecular cancer diagnostics. In molecular tumor boards, the detected genomic alterations are often discussed to decide the next treatment options for patients with cancer. With the increasing size and complexity of NGS panels, the discussion of these results becomes increasingly complex, especially if they are reported in a text-based form, as it is the standard in current molecular pathology. METHODS: We have developed the Molecular Tumor Profiling pilot (MTPpilot) webservice using HTML, PHP, JavaScript, and MySQL to support the clinical discussion of NGS results at molecular tumor boards. RESULTS: MTPpilot integrates various public genome, network, and cancer mutation databases with interactive visualization tools to assess the functional impact of mutations and support clinical decision making at tumor boards. CONCLUSION: MTPpilot is tailored for discussion of NGS gene panel results at molecular tumor boards. It is freely available as a webservice at MTPpilot.

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.

Developing a large-scale dataset of flood fatalities for territories in the Euro-Mediterranean region, FFEM-DB.

This data paper describes the multinational Database of Flood Fatalities from the Euro-Mediterranean region FFEM-DB that hosts data of 2,875 flood fatalities from 12 territories (nine of which represent entire countries) in Europe and the broader Mediterranean region from 1980 to 2020. The FFEM-DB database provides data on fatalities' profiles, location, and contributing circumstances, allowing researchers and flood risk managers to explore demographic, behavioral, and situational factors, as well as environmental features of flood-related mortality. The standardized data collection and classification methodology enable comparison between regions beyond administrative boundaries. The FFEM-DB is expandable, regularly updated, publicly available, and with anonymized data. The key advantages of the FFEM-DB compared to existing datasets containing flood fatalities are its high level of detail, data accuracy, record completeness, and the large sample size from an extended area.

Integrated Analysis Of Immunotherapy Treated Clear Cell Renal Cell Carcinomas: An Exploratory Study.

Molecular or immunological differences between responders and nonresponders to immune checkpoint inhibitors (ICIs) of clear cell renal cell carcinomas (ccRCCs) remain incompletely understood. To address this question, we performed next-generation sequencing, methylation analysis, genome wide copy number analysis, targeted RNA sequencing and T-cell receptor sequencing, and we studied frequencies of tumor-infiltrating CD8+ T cells, presence of tertiary lymphoid structures (TLS) and PD-L1 expression in 8 treatment-naive ccRCC patients subsequently treated with ICI (3 responders, 5 nonresponders). Unexpectedly, we identified decreased frequencies of CD8+ tumor-infiltrating T cells and TLS, and a decreased expression of PD-L1 in ICI responders when compared with nonresponders. However, neither tumor-specific genetic alterations nor gene expression profiles correlated with response to ICI or the observed immune features. Our results underline the challenge to stratify ccRCC patients for immunotherapy based on routinely available pathologic primary tumor material, even with advanced technologies. Our findings emphasize the analysis of pretreated metastatic tissue in line with recent observations describing treatment effects on the tumor microenvironment. In addition, our data call for further investigation of additional parameters in a larger ccRCC cohort to understand the mechanistic implications of the observed differences in tumor-infiltrating CD8+ T cells, TLS, and PD-L1 expression.