bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthetic lethal interaction between WEE1 and PKMYT1 is a target for multiple low-dose treatment of high-grade serous ovarian carcinoma
Authors: Benada Jan , Bulanova Daria , Azzoni Violette , Petrosius Valdemaras , Ghazanfar Saba , Wennerberg Krister , Sørensen Claus Storgaard 
Published: June 2023

Abstract
Ovarian cancer is driven by genetic alterations that necessitate protective DNA damage and replication stress responses through cell cycle control and genome maintenance. This creates specific vulnerabilities that may be exploited therapeutically. WEE1 kinase is a key cell cycle control kinase, and it has emerged as a promising cancer therapy target. However, adverse effects have limited its clinical progress, especially when tested in combination with chemotherapies. A strong genetic interaction between WEE1 and PKMYT1 led us to hypothesize that a multiple low-dose approach utilizing joint WEE1 and PKMYT1 inhibition would allow exploitation of the synthetic lethality. We found that the combination of WEE1 and PKMYT1 inhibition exhibited synergistic effects in eradicating ovarian cancer cells and organoid models at a low dose. The WEE1 and PKMYT1 inhibition synergistically promoted CDK activation. Furthermore, the combined treatment exacerbated DNA replication stress and replication catastrophe, leading to increase of the genomic instability and inflammatory STAT1 signalling activation. These findings suggest a new multiple low-dose approach to harness the potency of WEE1 inhibition through the synthetic lethal interaction with PKMYT1 that may contribute to the development of new treatments for ovarian cancer.
Leveraging Influenza Virus Surveillance From 2012 to 2015 to Characterize the Burden of Respiratory Syncytial Virus Disease in Canadian Adults ≥50 Years of Age Hospitalized With Acute Respiratory Illness
Authors: ElSherif May , Andrew Melissa K , Ye Lingyun , Ambrose Ardith , Boivin Guy , Bowie William , David Marie-Pierre , Gruselle Olivier , Halperin Scott A , Hatchette Todd F , Johnstone Jennie , Katz Kevin , Langley Joanne M , Loeb Mark , MacKinnon-Cameron Donna , McCarthy Anne , McElhaney Janet E , McGeer Allison , Poirier Andre , Pirçon Jean-Yves , Powis Jeff , Richardson David , Semret Makeda , Smith Stephanie , Smyth Daniel , Trottier Sylvie , Valiquette Louis , Webster Duncan , McNeil Shelly A , LeBlanc Jason J ,   for the Serious Outcomes Surveillance (SOS) Network of the Canadian Immunization Research Network (CIRN) and the Toronto Invasive Bacterial Diseases Network (TIBDN), ElSherif May , Andrew Melissa K , Ye Lingyun , Ambrose Ardith , Boivin Guy , Bowie William , David Marie-Pierre , Gruselle Olivier , Halperin Scott A , Hatchette Todd F , Johnstone Jennie , Katz Kevin , Langley Joanne M , Loeb Mark , MacKinnon-Cameron Donna , McCarthy Anne , McElhaney Janet E , McGeer Allison , Poirier Andre , Pirçon Jean-Yves , Powis Jeff , Richardson David , Semret Makeda , Smith Stephanie , Smyth Daniel , Trottier Sylvie , Valiquette Louis , Webster Duncan , McNeil Shelly A , LeBlanc Jason J 
Published: June 2023

Abstract

Background
Respiratory syncytial virus (RSV) disease in older adults is undercharacterized. To help inform future immunization policies, this study aimed to describe the disease burden in Canadian adults aged ≥50 years hospitalized with RSV.

Methods
Using administrative data and nasopharyngeal swabs collected from active surveillance among adults aged ≥50 years hospitalized with an acute respiratory illness (ARI) during the 2012–2013, 2013–2014, and 2014–2015 influenza seasons, RSV was identified using a respiratory virus multiplex polymerase chain reaction test to describe the associated disease burden, incidence, and healthcare costs.

Results
Of 7797 patients tested, 371 (4.8%) were RSV positive (2.2% RSV-A and 2.6% RSV-B). RSV prevalence varied by season from 4.2% to 6.2%. Respiratory virus coinfection was observed in 11.6% (43/371) of RSV cases, with influenza A being the most common. RSV hospitalization rates varied between seasons and increased with age, from 8–12 per 100 000 population in adults aged 50–59 years to 174–487 per 100 000 in adults aged ≥80 years. The median age of RSV cases was 74.9 years, 63.7% were female, and 98.1% of cases had ≥1 comorbidity. Among RSV cases, the mean length of hospital stay was 10.6 days, 13.7% were admitted to the intensive care unit, 6.4% required mechanical ventilation, and 6.1% died. The mean cost per RSV case was $13 602 (Canadian dollars) but varied by age and Canadian province.

Conclusions
This study adds to the growing literature on adult RSV burden by showing considerable morbidity, mortality, and healthcare costs in hospitalized adults aged ≥50 years with ARIs such as influenza.
Clinical Risk Scores to Predict Nonsusceptibility to Trimethoprim-Sulfamethoxazole, Fluoroquinolone, Nitrofurantoin, and Third-Generation Cephalosporin Among Adult Outpatient Episodes of Complicated Urinary Tract Infection
Authors: Lodise Thomas P , Chen Lie Hong , Wei Rong , Im Theresa M , Contreras Richard , Bruxvoort Katia J , Rodriguez Mauricio , Friedrich Larry , Tartof Sara Y 
Published: June 2023

Abstract

Background
Clinical risk scores were developed to estimate the risk of adult outpatients having a complicated urinary tract infection (cUTI) that was nonsusceptible to trimethoprim-sulfamethoxazole (TMP-SMX), fluoroquinolone, nitrofurantoin, or third-generation cephalosporin (3-GC) based on variables available on clinical presentation.

Methods
A retrospective cohort study (1 December 2017–31 December 2020) was performed among adult members of Kaiser Permanente Southern California with an outpatient cUTI. Separate risk scores were developed for TMP-SMX, fluoroquinolone, nitrofurantoin, and 3-GC. The models were translated into risk scores to quantify the likelihood of nonsusceptibility based on the presence of final model covariates in a given cUTI outpatient.

Results
A total of 30 450 cUTIs (26 326 patients) met the study criteria. Rates of nonsusceptibility to TMP-SMX, fluoroquinolone, nitrofurantoin, and 3-GC were 37%, 20%, 27%, and 24%, respectively. Receipt of prior antibiotics was the most important predictor across all models. The risk of nonsusceptibility in the TMP-SMX model exceeded 20% in the absence of any risk factors, suggesting that empiric use of TMP-SMX may not be advisable. For fluoroquinolone, nitrofurantoin, and 3-GC, clinical risk scores of 10, 7, and 11 predicted a ≥20% estimated probability of nonsusceptibility in the models that included cumulative number of prior antibiotics at model entry. This finding suggests that caution should be used when considering these agents empirically in patients who have several risk factors present in a given model at presentation.

Conclusions
We developed high-performing parsimonious risk scores to facilitate empiric treatment selection for adult outpatients with cUTIs in the critical period between infection presentation and availability of susceptibility results.
Variations in Genomic Testing in Non-small Cell Lung Carcinoma: A Healthcare Professional Survey of Current Practices in the UK
Authors: Baijal Shobhit , Crosbie Philip , Fenemore Jackie , Desai Ketul 
Published: June 2023

Abstract
This survey aims to understand the current UK practice for non-small cell lung carcinoma (NSCLC) and identify barriers that may impact patient treatment and outcomes. In March–June 2021, 57 interviews were conducted with healthcare professionals involved in the secondary care management of patients with NSCLC. Most respondents performed genetic testing at onsite and non-genomic laboratory hub (GLH) offsite locations. The most common genetic tests were EGFR T790M variant (100%), EGFR exon 18-21 covered (95%) and BRAF (93%). No targeted therapy (TT) available (69%), lack of access to a TT (54%) or excessive molecular testing turnaround times (39%) were the most common reasons for using an immuno-oncology therapy over a TT in the first-line setting. The survey highlights variation in mutation testing practices across the UK, which may impact treatment decisions and contribute to health outcome inequality.
Avelumab in Patients With Metastatic Colorectal Cancer
Authors: Redman Jason M , O’Sullivan Coyne Geraldine , Reed Clay T , Madan Ravi A , Strauss Julius , Steinberg Seth J , Marté Jennifer , Cordes Lisa , Heery Christopher , Gulley James L 
Published: June 2023

Abstract

Background
Metastatic colorectal cancer (mCRC) is incurable, and median overall survival is less than 2½ years. Although monoclonal antibodies that block PD-1/PD-L1 interactions are active in microsatellite unstable/mismatch repair deficient tumors, a growing dataset shows that most patients with microsatellite stable/mismatch repair proficient tumors will not benefit from the blockade of PD-1/PD-L1 interactions. Here we present results from patients with mCRC (n = 22) treated with the anti-PD-L1 monoclonal antibody avelumab.

Methods
Patients received treatment on a phase I, open-label, dose-escalation trial via a consecutive parallel-group expansion in colorectal cancer. Patients aged 18 years and older with mCRC measurable by RECIST v1.1 who had received at least 1 line of systemic therapy for metastatic disease enrolled. Patients with prior immune checkpoint inhibitor treatment were excluded. Patients received avelumab 10 mg/kg intravenously every 2 weeks. The primary endpoint was the objective response rate.

Results
Twenty-two participants received treatment from July 2013 to August 2014. There were no objective responses and median progression-free survival was 2.1 months (95% CI: 1.4-5.5 months). There were 5 grade 3 treatment-related adverse events: GGT elevation (n = 2), PRESS (n = 1), lymphopenia (n = 1), and asymptomatic amylase/lipase elevation (n = 1).

Conclusion
As demonstrated with other anti-PD-1/PD-L1 monoclonal antibodies, avelumab is not active in unselected patients with mCRC (ClinicalTrials.gov Identifier: NCT01772004).
Diagnosis, Treatment, and Prognosis of Patients with Primary Familial Gastrointestinal Stromal Tumor: A Case Report and Literature Review
Authors: Yan Miao , Lin Jianghua , Shu Man , Luo Yanji , Sun Kaiyu , Yang Shaohua , Zhang Xinhua 
Published: June 2023

Abstract
Gastrointestinal stromal tumors are the most common mesenchymal tumors of the digestive tract, most of which are sporadic, and familial GISTs with germline mutations are rarely seen. Here, we report a 26-year-old female with a germline p. W557R mutation in exon 11 of the KIT gene. The proband and her father and sister presented with multifocal GIST and pigmented nevi. All 3 patients underwent surgery and imatinib therapy. To date, only 49 kindreds with germline KIT mutations and 6 kindreds with germline PDGFRA mutations have been reported. Summarizing the reported kindreds, the majority of familial GISTs manifest as multiple primary GISTs complicated with special clinical manifestations, including cutaneous hyperpigmentation, dysphagia, mastocytosis, inflammatory fibrous polyps, and large hands. Familial GISTs are generally thought to exhibit TKI sensitivity similar to that of sporadic GISTs with the same mutation.
Plastid dsRNA transgenes trigger phased small RNA-based gene silencing of nuclear-encoded genes
Authors: Bélanger Sébastien , Kramer Marianne C , Payne Hayden A , Hui Alice Y , Slotkin R Keith , Meyers Blake C , Staub Jeffrey M 
Published: June 2023

Abstract
Plastid transformation technology has been widely used to express traits of potential commercial importance, though the technology has been limited to traits that function while sequestered in the organelle. Prior research indicates that plastid contents can escape from the organelle, suggesting a possible mechanism for engineering plastid transgenes to function in other cellular locations. To test this hypothesis, we created tobacco (Nicotiana tabacum cv. Petit Havana) plastid transformants that express a fragment of the nuclear-encoded Phytoene desaturase (PDS) gene capable of catalyzing post-transcriptional gene silencing if RNA escapes into the cytoplasm. We found multiple lines of direct evidence that plastid-encoded PDS transgenes affect nuclear PDS gene silencing: knockdown of the nuclear-encoded PDS mRNA and/or its apparent translational inhibition, biogenesis of 21-nucleotide (nt) phased small interfering RNAs (phasiRNAs), and pigment-deficient plants. Furthermore, plastid-expressed dsRNA with no cognate nuclear-encoded pairing partner also produced abundant 21-nt phasiRNAs in the cytoplasm, demonstrating that a nuclear-encoded template is not required for siRNA biogenesis. Our results indicate that RNA escape from plastids to the cytoplasm occurs generally, with functional consequences that include entry into the gene silencing pathway. Furthermore, we uncover a method to produce plastid-encoded traits with functions outside of the organelle and open additional fields of study in plastid development, compartmentalization, and small RNA biogenesis.
On the evolution of the plant phytochrome chromophore biosynthesis
Authors: Frascogna Federica , Ledermann Benjamin , Hartmann Jana , Pérez Patallo Eugenio , Zeqiri Fjoralba , Hofmann Eckhard , Frankenberg-Dinkel Nicole 
Published: June 2023

Abstract
Phytochromes are biliprotein photoreceptors present in plants, algae, certain bacteria, and fungi. Land plant phytochromes use phytochromobilin (PΦB) as the bilin chromophore. Phytochromes of streptophyte algae, the clade within which land plants evolved, employ phycocyanobilin (PCB), leading to a more blue-shifted absorption spectrum. Both chromophores are synthesized by ferredoxin-dependent bilin reductases (FDBRs) starting from biliverdin IXα (BV). In cyanobacteria and chlorophyta, BV is reduced to PCB by the FDBR phycocyanobilin:ferredoxin oxidoreductase (PcyA), whereas, in land plants, BV is reduced to PФB by phytochromobilin synthase (HY2). However, phylogenetic studies suggested the absence of any ortholog of PcyA in streptophyte algae and the presence of only PФB biosynthesis-related genes (HY2). The HY2 of the streptophyte alga Klebsormidium nitens (formerly Klebsormidium flaccidum) has already indirectly been indicated to participate in PCB biosynthesis. Here, we overexpressed and purified a His6-tagged variant of K. nitens HY2 (KflaHY2) in Escherichia coli. Employing anaerobic bilin reductase activity assays and coupled phytochrome assembly assays, we confirmed the product and identified intermediates of the reaction. Site-directed mutagenesis revealed 2 aspartate residues critical for catalysis. While it was not possible to convert KflaHY2 into a PΦB-producing enzyme by simply exchanging the catalytic pair, the biochemical investigation of 2 additional members of the HY2 lineage enabled us to define 2 distinct clades, the PCB-HY2 and the PΦB-HY2 clade. Overall, our study gives insight into the evolution of the HY2 lineage of FDBRs.
ALBINO EMBRYO AND SEEDLING is required for RNA splicing and chloroplast homeostasis in Arabidopsis
Authors: An Hongqiang , Ke Xiaolong , Li Lu , Liu Yantong , Yuan Sihui , Wang Qiuyu , Hou Xin , Zhao Jie 
Published: June 2023

Abstract
Pentatricopeptide repeat (PPR) proteins form a large protein family and have diverse functions in plant development. Here, we identified an ALBINO EMBRYO AND SEEDLING (AES) gene that encodes a P-type PPR protein expressed in various tissues, especially the young leaves of Arabidopsis (Arabidopsis thaliana). Its null mutant aes exhibited a collapsed chloroplast membrane system, reduced pigment content and photosynthetic activity, decreased transcript levels of PEP (plastid-encoded polymerase)–dependent chloroplast genes, and defective RNA splicing. Further work revealed that AES could directly bind to psbB-psbT, psbH-petB, rps8-rpl36, clpP, ycf3, and ndhA in vivo and in vitro and that the splicing efficiencies of these genes and the expression levels of ycf3, ndhA, and cis-tron psbB-psbT-psbH-petB-petD decreased dramatically, leading to defective PSI, PSII, and Cyt b6f in aes. Moreover, AES could be transported into the chloroplast stroma via the TOC–TIC channel with the assistance of Tic110 and cpSRP54 and may recruit HCF244, SOT1, and CAF1 to participate in the target RNA process. These findings suggested that AES is an essential protein for the assembly of photosynthetic complexes, providing insights into the splicing of psbB operon (psbB-psbT-psbH-petB-petD), ycf3, and ndhA, as well as maintaining chloroplast homeostasis.
Pectin modifications promote haustoria development in the parasitic plantPhtheirospermum japonicum
Authors: Leso Martina , Kokla Anna , Feng Ming , Melnyk Charles W 
Published: June 2023

AbstractParasitic plants are globally prevalent pathogens with important ecological functions but also potentially devastating agricultural consequences. Common to all parasites is the formation of the haustorium which requires parasite organ development and tissue invasion into the host. Both processes involve cell wall modifications. Here, we investigated a role for pectins during haustorium development in the facultative parasitic plant Phtheirospermum japonicum. Using transcriptomics data from infected Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), we identified genes for multiple P. japonicum pectin methylesterases (PMEs) and their inhibitors (PMEIs) whose expression was upregulated by haustoria formation. Changes in PME and PMEI expression were associated with tissue-specific modifications in pectin methylesterification. While de-methylesterified pectins were present in outer haustorial cells, highly methylesterified pectins were present in inner vascular tissues, including the xylem bridge that connects parasite to host. Specifically blocking xylem bridge formation in the haustoria inhibited several PME and PMEI genes from activating. Similarly, inhibiting PME activity using chemicals or by overexpressing PMEI genes delayed haustoria development. Our results suggest a dynamic and tissue-specific regulation of pectin contributes to haustoria initiation and to the establishment of xylem connections between parasite and host.
Increasing the Acceptance of Smartphone-Based Data Collection
Authors: Wenz Alexander , Keusch Florian 
Published: June 2023

Abstract
To study human behavior, social scientists are increasingly collecting data from mobile apps and sensors embedded in smartphones. A major challenge of studies implemented on general population samples, however, is that participation rates are rather low. While previous research has started to investigate the factors affecting individuals’ decision to participate in such studies, less is known about features of the study design which are under the researcher’s control and can increase the acceptance of smartphone-based data collection methods. Guided by the Technology Acceptance Model, we varied study characteristics in a vignette experiment to examine their effect on individuals’ willingness to download a research app on their smartphone. Data were collected from 1,876 members of the NORC AmeriSpeak Panel, a probability-based panel of the general population aged 18+ in the United States. Respondents were randomly assigned to eight vignettes and, after each vignette, were asked to rate their willingness to participate in the described hypothetical study. The results show that individuals are more willing to participate in smartphone-based studies where they have some control over the data collection process, by having the option either to temporarily switch off the data collection or to review the data before submission. Furthermore, they are more willing to participate in research to which they are invited via postal letter rather than receiving a postal letter plus a phone call from an interviewer who walks them through the app installation. Finally, unconditional incentives increase their willingness to engage with smartphone-based data collection over conditional incentives.
Inheritance of Partial Resistance to Isolate VdLs17 of Verticillium dahliae Within Lactuca spp.
Authors: Nayak Santosh , Richardson Kelley 
Published: June 2023

Lettuce (Lactuca sativa L.) production is greatly threatened by Verticillium wilt, which is caused by three pathogenic races (races 1, 2, and 3) of the soilborne fungus Verticillium dahliae. Race 1 is predominant, and resistant varieties that provide full protection against it are commercially available. However, heavily relying on race 1-resistant cultivars could shift the population towards resistance-breaking isolates and impact the durability of plant resistance. This study determined the inheritance of partial resistance to isolate VdLs17 of V. dahliae within Lactuca spp. using 258 F2:3 progeny generated from a cross between two partially resistant accessions, 11G99 (L. serriola) and PI 171674 (L. sativa). Eight experiments were performed under greenhouse and growth room conditions across 3 years using a randomized complete block design, and segregation analysis was conducted to determine the inheritance pattern. The results indicate that partial resistance to isolate VdLs17 of V. dahliae is conditioned by a two-major-gene genetic model with additive-dominance-epistatic effects. Transgressive segregants were infrequent but observed in both directions, indicating that favorable and adverse alleles are dispersed in both parents. Combining favorable alleles of these two partially resistant parents appears to be challenging because of epistatic effects and a significant role of environment in disease severity. The probability of capturing favorable additive genes could be maximized by generating and evaluating a large population and making selections at late generations. This study provides valuable insights into the inheritance pattern of partial resistance to isolate VdLs17 of V. dahliae that will be helpful in designing efficient breeding strategies in lettuce. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license .
Clinicopathological significance of unraveling mitochondrial pathway alterations in non‐small‐cell lung cancer
Authors: Hertweck Kate L. , Vikramdeo Kunwar S. , Galeas Jose N. , Marbut Stephen M. , Pramanik Paramahansa , Yunus Furhan , Singh Seema , Singh Ajay P. , Dasgupta Santanu 
Published: June 2023

AbstractEarly detection, accurate monitoring, and therapeutics are major problems in non‐small‐cell lung cancer (NSCLC) patients. We identified genomic copy number variation of a unique panel of 40 mitochondria‐targeted genes in NSCLCs (GEOGSE #29365). Validation of mRNA expression of these molecules revealed an altered panel of 34 genes in lung adenocarcinomas (LUAD) and 36 genes in lung squamous cell carcinomas (LUSC). In the LUAD subtype (n = 533), we identified 29 upregulated and 5 downregulated genes, while in the LUSC subtype (n = 502), a panel of 30 upregulated and 6 downregulated genes were discovered. The majority of these genes are associated with mitochondrial protein transport, ferroptosis, calcium signaling, metabolism, OXPHOS function, TCA cycle, apoptosis, and MARylation. Altered mRNA expression of SLC25A4, ACSF2, MACROD1, and GCAT was associated with poor survival of the NSCLC patients. Progressive loss of SLC25A4 protein expression was confirmed in NSCLC tissues (n = 59), predicting poor survival of the patients. Forced overexpression of SLC25A4 in two LUAD cell lines inhibited their growth, viability, and migration. A significant association of the altered mitochondrial pathway genes with LC subtype‐specific classical molecular signatures was observed, implicating the existence of nuclear‐mitochondrial cross‐talks. Key alteration signatures shared between LUAD and LUSC subtypes including SLC25A4, ACSF2, MACROD1, MDH2, LONP1, MTHFD2, and CA5A could be helpful in developing new biomarkers and therapeutics.