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Background The landscape of non-small cell lung cancer (NSCLC) therapy is rapidly changing. This analysis aimed to understand patient characteristics, diagnosis and treatment patterns in patients with metastatic NSCLC (mNSCLC) without EGFR and ALK mutations across five European countries. Methods Data were drawn from the Adelphi NSCLC Disease Specific Programme™, a point-in-time survey of oncologists/pulmonologists and their consulting patients in France, Germany, Italy, Spain and UK. Physicians completed record forms (RFs) for the next six consecutive consulting patients with advanced NSCLC, who then voluntarily completed questionnaires. As an oversample, physicians provided a further ten RFs specifically for patients with EGFR -wild-type mNSCLC: five patients diagnosed before March 2020 (pre-SARS-CoV-2 [COVID-19]) and five patients diagnosed from March 2020 (during COVID-19). Only EGFR -wild-type/ ALK -wild-type patients were included for analysis. Results Mean (standard deviation [SD]) age for 1073 patients with EGFR -wild-type/ ALK -wild-type mNSCLC was 66.2 (8.9) years, 65.2% were male and 63.7% had adenocarcinoma. Level of PD-L1 expression at advanced diagnosis was < 1% for 23.1% of patients, 1–49% for 40.9% and ≥ 50% for 36.0%. Most common first-line (1L) advanced treatment was chemotherapy only (36.9%), immunotherapy monotherapy (30.5%) or immunotherapy + chemotherapy (27.6%). Of 158 patients who had progressed beyond 1L therapy, the mean (SD) time-to-treatment discontinuation was 5.1 (4.3) months; 75.9% of whom completed their 1L treatment as intended. A complete response was achieved by 6.7% and a partial response by 69.2% of patients. Of 38 patients who discontinued 1L treatment early, disease progression was reported for 73.7%. Quality of life (QoL) reported by patients was generally lower than normative reference values. Of 2373 oversample patients, physicians reported management changes for 34.7% due to COVID-19, ranging from 19.6% in Germany to 79.7% in the UK. Immunotherapy was prescribed as 1L NSCLC treatment during COVID-19 for 64.2% ( n  = 786) of patients and pre-COVID-19, for 47.8% ( n  = 549). Conclusions Real-world treatment patterns suggest that chemotherapy use remains high despite guidelines recommending immunotherapy-based 1L treatment for mNSCLC. QoL reported by patients was generally lower than population reference values. Not implying causality, 1L immunotherapy use was higher during COVID-19 than pre-COVID-19, and the UK saw the biggest impact to patient management due to COVID-19.

Weighted projective lines, introduced by Geigle and Lenzing in 1987, are important objects in representation theory. They have tilting bundles, whose endomorphism algebras are the canonical algebras introduced by Ringel. The aim of this paper is to study their higher dimensional analogs. First, we introduce a certain class of commutative Gorenstein rings

Aims To reveal the effects of intra‐ and inter‐tumoral heterogeneity on characteristics of primary IDH‐wild type glioblastoma cells. Methods Single‐cell RNA‐seq data were acquired from the GEO database, and bulk sample transcriptome data were downloaded from the TCGA database with clinical information. Neoplastic subtype and glioma stem‐like cells (GSCs) were identified by matching 5000 random virtual samples based on ssGSEA. CNV was inferred to compare the heterogeneity among patients and subtypes by infercnv. Transition direction was inferred by RNA velocity, and lineage trajectory was inferred by monocle. Regulon network of cells was analyzed by SCENIC, and cell communication was identified by CellPhoneDB. Results Glioblastoma (GBM) cells could be divided into four subtypes by Verhaak classifier. However, classification of three subtypes (except NE subtype) was more suitable for GBM cells, and Verhaak classifier has difficulty in distinguishing GSCs. GBM heterogeneity and GBM cells’ regulon network were mainly influenced by inter‐tumoral heterogeneity. Within the same patient, different subclones exist in the same subtype of cells whose transition direction could be predicted by regulon similarity. Apart from inter‐tumoral heterogeneity, different subtype of cells share common subtype‐specific cell‐cell communications. Conclusions Inter‐tumoral heterogeneity contributes mainly to GBM heterogeneity and cell molecular characteristics. However, the same subtype of cells shared cell communication similarities.

In patients with gastrointestinal stromal tumors (GIST), it has become mandatory to determine the driver mutation in order to predict the response to standard treatment with tyrosine kinase inhibitors (TKI). A total of 10-15% of all GIST lack activating mutations in KIT proto-oncogene, receptor tyrosine kinase (KIT)/platelet-derived growth factor receptor alpha (PDGFRA) and have been classified as KIT/PDGFRA wild-type (WT) GIST. They are characterized by poor response to TKI. From a group of 119 metastatic GIST patients, 17 patients with KIT/PDGFRA/BRAF WT GIST as determined by reverse transcription-quantitative (RT-q) PCR and Sanger sequencing were profiled by a targeted next-generation sequencing (NGS) approach and their treatment outcome was assessed. In the present study, 41.2% of patients as KIT/PDGFRA/BRAF WT GIST examined with RT-qPCR and Sanger sequencing were confirmed to be carriers of pathogenic KIT/PDGFRA mutations by NGS and were responsive to TKI. The percentage of genuinely KIT/PDGFRA WT GIST in the present study thereby dropped from the initial 14.3% detected with the RT-qPCR and Sanger sequencing to 7.6% after NGS. Their outcome was universally poor. The reliability of RT-qPCR and direct Sanger sequencing results in this setting is therefore insufficient and it is recommended that NGS becomes a requirement for treatment decision at least in KIT/PDGFRA/BRAF WT GIST as determined by RT-qPCR and Sanger sequencing.

Epidermal growth factor receptor‐targeted (EGFR‐targeted) therapies show promise for non‐small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild‐type NSCLC. A genome‐wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild‐type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild‐type NSCLC cells. Additionally, PAICS silencing led to cell‐cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild‐type NSCLC. PAICS silencing also caused DNA damage and cell‐cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K–AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild‐type NSCLC and represents a potential therapeutic target for this disease. Genome‐wide CRISPR–Cas9 screening identified PAICS as a potential target for EGFR wild‐type NSCLC. Increased PAICS expression in NSCLC tissues correlates with poor prognosis. PAICS knockdown markedly reduces in vitro and in vivo proliferation of EGFR wild‐type NSCLC cells, inducing cell‐cycle arrest through interaction with DNA repair genes. This highlights PAICS as an oncogenic factor and a potential therapeutic target for EGFR wild‐type NSCLC.

Aims Transthyretin amyloid cardiomyopathy (ATTR‐CM) is a progressive, fatal disorder that remains underdiagnosed. The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR‐ACT) was the first large clinical trial to include both wild‐type (ATTRwt) and hereditary (ATTRv) patients. A description of the natural history of ATTR‐CM, utilizing data from placebo‐treated patients in ATTR‐ACT, will provide a greater understanding of presentation and progression of ATTR‐CM and may aid in disease awareness, earlier diagnosis and treatment monitoring. Methods and results Changes in clinical endpoints (mortality, cardiovascular [CV]‐related hospitalizations, 6‐min walk test [6MWT] distance and Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ‐OS] score) from baseline to Month 30 in the 177 patients (134 ATTRwt, 43 ATTRv) who received placebo in ATTR‐ACT were assessed. ATTRwt patients tended to have less severe disease at baseline. Over the duration of ATTR‐ACT, there were 76 (42.9%) all‐cause deaths, and 107 (60.5%) patients had a CV‐related hospitalization. There was a lower proportion of all‐cause deaths in ATTRwt (49, 36.6%) than ATTRv (27, 62.8%). There was a similar, steady decline in mean (SD) 6MWT distance from baseline to Month 30 in ATTRwt (93.9 [93.7] m) and ATTRv (89.1 [107.2] m) patients. The decline in mean (SD) KCCQ‐OS score was less severe in ATTRwt (13.8 [20.7]) than ATTRv (21.0 [26.4]) patients. Conclusions Patients with ATTR‐CM experience a severe, progressive disease. In ATTR‐ACT, placebo‐treated patients with ATTRv, compared with ATTRwt, had more severe disease at baseline, and their disease progressed more rapidly as shown by mortality, hospitalizations and quality of life over time.

•Complete genomes of six 1978/79 fetal and respiratory BoHV-1 isolates were sequenced.•Vaccine-derived strains, WTs, and one vaccine/WT recombinant virus were recovered.•Fetal recombinant had a WT genome with two blocks of vaccine-derived sequences.•Evidence that recombination can occur naturally between BoHV-1 vaccine and WT viruses.•Underscores importance of gene-deleted marker vaccines recombining and losing markers. Bovine herpesvirus type 1 (BoHV-1) causes various disease syndromes in cattle including respiratory disease and abortions. During an investigation into the potential role of BoHV-1 modified-live vaccines (MLV) causing diseases in cattle, we performed whole genome sequencing on six BoHV-1 field strains isolated at Cornell Animal Health Diagnostic Center in the late 1970s. Three isolates (two respiratory and a fetal) were identified as vaccine-derived isolates, having SNP patterns identical to that of a previously sequenced MLV virus that exhibited a deleted US2 and truncated US1.67 genes. Two other isolates (a respiratory and a fetal) were categorized as wild-type (WT) viruses based on their unique SNP pattern that is distinct from MLV viruses. The sixth isolate from an aborted fetus was a recombinant virus with 62% of its genome exhibiting SNPs identical to one of the above-mentioned WT viruses also recovered from an aborted fetus. The remaining 38% consisted of two blocks of sequences derived from the MLV virus. The first block replaced the UL9-UL19 region, and the second vaccine-derived sequence block encompassed all the genes within the unique short region and the internal/terminal repeats containing the regulatory genes BICP4 and BICP22. This is confirmatory evidence that recombination between BoHV-1 MLV and WT viruses can occur under natural conditions and cause disease. It is important in that it underscores the potential for the glycoprotein E negative (gE−) marker vaccine used to eradicate BoHV-1 in some countries, to recombine with virulent field strains allowing them to capture the gE− marker, thereby endangering the control and eradication programs.

In this study, we analyzed the BK polyomavirus (BKPyV) genome derived from three rodent cell lines established from experimentally induced tumors by injecting BKPyV into newborn rodents. Three cell lines (Vn‐324, In‐1024, and Vn1919) were recently deposited in the JCRB Cell Bank (Japanese Collection of Research Bioresource Cell Bank). Vn‐324 was established from a hamster choroid plexus papilloma induced by BKPyV Gardner strain wild‐type 501 (wt‐501). This cell line was reported to be negative for the large T‐antigen using indirect immunofluorescence. In this study, we examined the large T‐antigen expression using the reverse‐transcriptase‐polymerase chain reaction (RT‐PCR). In‐1024 cells were established from hamster insulinoma. The strain of BKPyV from which were induced has not been reported. Vn1919 was established from a mouse ependymoma induced by the plaque morphology mutant 522 (pm‐522). The noncoding control region (NCCR) of BKPyV derived from Vn‐324 genomic DNA and wt‐501 had the same structure, whereas the NCCR of BKPyV derived Vn1919 genomic DNA and pm‐522 had the same structure. But the NCCR derived In‐1024 was unique. We revealed that BKPyV derived from In‐1024 genomic DNA had a large deletion in the viral proteins 1, 2, and 3 (VP1,(VP1, VP2, and VP3) coding region. This variant may be a proliferation‐defective mutant, which was expanded in human embryonic kidney cells with other mutants. These findings provide insights into the role of NCCR mutations in viral oncogenesis. In this study, we analyzed the BK polyomavirus (BKPyV) genome derived from three rodent cell lines established from BKPyV induced tumors. BKPyV derived one cell line had a large deletion. The noncoding control region (NCCR) of BKPyV derived from these cell lines had the same structure as viruses induced tumors.

According to the review of the literature, rubella virus‐related granuloma is an entity first described in 2014 mainly affecting children with primary immune deficiencies infected with the rubella vaccine strain. The development of rubella virus‐associated granulomas seems to be related to a defect in cellular immunity and their severity varies from a simple cutaneous lesion to deep visceral involvement in some patients. Since then, this type of granuloma has been described in immunocompetent adults, including two cases involving a wild‐type strain of the virus (genotype 2). We report the case of a 70‐year‐old man had suffered from a granuloma of the leg for almost 40 years, in the absence of immunodeficiency. The assessment of the skin granuloma revealed a positive polymerase chain reaction for a wild‐type rubella virus genotype 1a. Genetic studies performed using whole exome sequencing suggest that the disease is due to a homozygous splice site mutation in the ITK gene.